Compositions and methods for antibodies targeting factor p

ABSTRACT

The present invention relates to antibodies or antigen binding fragments thereof that bind to complement Factor P and used thereof as well as combinations of anti-Factor P antibodies with antibodies or antigen binding fragments thereof that bind to complement component 5 (C5).

BACKGROUND OF THE INVENTION

Age related macular degeneration (AMD) is a progressive disease and aleading cause of vision loss and blindness in Americans aged 65 andolder. AMD primarily affects the macula; a part of the retinaresponsible for high visual acuity needed to read or drive. The majorityof AMD patients suffer from an early stage of the disease which ischaracterized by the presence of extracellular retinal deposits calleddrusen. Drusen are extracellular retinal deposits of cell debris,inflammatory mediators, and extracellular matrix components. The latestages of AMD manifest as a dry or wet form, both are associated withvision loss. Dry AMD, also known as geographic atrophy, appears onophthalmoscopic examination as clearly demarcated regions correspondingto local areas of retinal pigmented epithelium (RPE) loss. Wet AMD isassociated with neovascularization of the choriod, causing a loss ofintegrity in Bruch's membrane and vessel growth in the retina, wherethey can often hemorrhage. This leakage causes permanent damage toretinal cells which die off and create blind spots in the centralvision.

The innate human system is composed of the complement pathway. Thecomplement pathway serves to defend against pyogenic bacterial infectionbridging innate and adaptive immunity; and disposing of products ofimmune complexes and inflammatory injury. The complement is a system ofmore than 30 proteins involved in cascade reactions in plasma and cellsurfaces. The complement system and its complement components areinvolved in various immune processes. For example, complement C5b-9complex, also termed the terminal complex or the membrane attack complex(MAC), plays an important role in cell death by inducing membranepermeability damages.

There are three known complement activation pathways: the classical,lectin, and alternative pathways. All three pathways lead to thecleavage of C3 by C3 convertase and subsequent cleavage of C5 by the C5convertase, releasing C3a, C5a, and C5b. Factor P is a key regulator ofthe alternative complement pathway. It is proposed to have two majorfunctions in viva First, Factor P stabilizes the C3 and C5 convertasesby binding to C3b of the convertase enzyme and thereby prolongs the halflife of C3 convertase. Second, Factor P may determine which cells willbe lysed by attaching to a cell surface and functioning as a template onwhich convertases can form, leading to activation of the alternativecomplement pathway and lysis of the cell.

Recent work has demonstrated that complement components C3 and C5 areprincipal constituents of drusen in patients with AMD. Mulling, R. F. etal. (2000) FASEB J 14, 835-46 Their presence as well as that of themembrane attack complex (MAC) C5b-9 and other acute phase reactantproteins in RPE cells overlying drusen has been speculated to beinvolved in the process that can trigger complement activation andformation of MAC. Johnson, L et al. (2001) Exp Eye Res 73, 887-896.Thus, there is growing evidence that complement components are more thanmere mediators of innate immunity.

Nutritional intervention has been prescribed to inhibit progression ofdry AMD to wet AMD. At present the only FDA approved treatments for wetAMD include photodynamic therapy (PDT), an anti-VEGF aptamer, such aspegaptanib, and anti-VEGF antibodies, ranibizumab. These drugs ortherapies are typically administered to patients who have alreadysuffered substantial vision loss.

There remains a need to develop an effective treatment for AMD,particularly dry AMD to replace or supplement current treatments.Particularly, there is a need for treatments which can provide earlydetection, prevention or restoration of vision loss.

SUMMARY OF THE INVENTION

The present invention relates to an isolated antibody, or antigenbinding fragment thereof, that binds to human or cynomolgus Factor P,wherein said antibody binds to the TSR5 domain (SEQ ID NO: 406). Forexample, the antibodies, or antigen binding fragments described hereinbind to a region of the TSR5 domain comprising the sequence of SEQ IDNO: 407, more specifically said antibodies also bind a region of theFactor P TSR5 domain comprising the amino acid sequence KSISC (SEQ IDNO: 408). In certain embodiments, the isolated antibodies, or antigenbinding fragments thereof, bind to a Factor P epitope comprising theamino acid sequence of SEQ ID NO: 407. In other embodiments, theisolated antibodies, or antigen binding fragments thereof, bind to aFactor P epitope comprising the amino acid sequence of SEQ ID NO: 408.

The isolated antibodies, or antigen binding fragments, described hereinbind Factor P, with a KD of less than or equal to 1.2 nM. For example,the isolated antibodies or antigen binding fragments described hereinmay bind to human or cynomolgus Factor P with a KD of less than or equalto 1.1 nM, less than or equal to 1 nM, less than or equal to 600 pM,less than or equal to 500 pM, less than or equal to 400 pM, less than orequal to 300 pM, less than or equal to 200 pM, less than or equal to 100pM, less than or equal to 75 pM, less than or equal to 50 pM, less thanor equal to 40 pM, less than or equal to 30 pM, less than or equal to 20pM, or less than or equal to 10 pM.

The binding affinity of isolated antibodies and antigen bindingfragments described herein can be determined by solution equilibriumtitration (SET). Methods for SET are known in the art and are describedin further detail below. Alternatively, binding affinity of the isolatedantibodies, or fragments, described herein can be determined by Biacoreassay. Methods for Biacore kinetic assays are know in the art and aredescribed in further detail below.

The isolated antibodies and antigen binding fragments described hereincan be used to inhibit the alternative complement pathway. For example,an isolated antibody or antigen binding fragment thereof can inhibit thealternative complement pathway as measure by an in vitro hemolytic assaywith an IC50 of less than or equal to 25 nm, less than or equal to 20nM, less than or equal to 16 nM, less than or equal to 15 nM, less thanor equal to 14 nM, less than or equal to 13 nM, less than or equal to 12nM, less than or equal to 11 nM, less than or equal to 10 nM, less thanor equal to 9 nM, less than or equal to 8 nM, less than or equal to 7nM. More specifically, an isolated antibody or antigen binding fragmentthereof as described herein can inhibit the alternative complementpathway in human as measure by an in vitro hemolytic assay with an IC50of less than or equal to 16 nm, or less than or equal to 9 nm.

An isolated antibody or antigen binding fragment thereof as describedherein can inhibit the alternative complement pathway as measure by anin vitro C3b deposition assay with an IC50 of less than or equal to 10nm, less than or equal to 7 nM, less than or equal to 6 nM, less than orequal to 5 nM, less than or equal to 4 nM, less than or equal to 3 nM,less than or equal to 2 nM, less than or equal to 1 nM, less than orequal to 15 nM, less than or equal to 1 nM, less than or equal to 0.5nM, or less than or equal to 0.1 nM. More specifically, an isolatedantibody or antigen binding fragment thereof as described herein caninhibit the alternative complement pathway in human as measure by an invitro C3b deposition assay with an IC50 of less than or equal to 3 nm,or less than or equal to 2 nM.

An isolated antibody or antigen binding fragment thereof as describedherein can inhibit the alternative complement pathway with an IC50 ofless than or equal to 25 nm, less than or equal to 20 nM, less than orequal to 15 nM, less than or equal to 10 nM, less than or equal to 9 nM,less than or equal to 8 nM, less than or equal to 7 nM, or less than orequal to 6 nM, as measure by deposition of the complement membraneattack complex. More specifically, an isolated antibody or fragmentthereof as described herein can inhibit the alternative complementpathway in human with an IC50 of less than or equal to 25 nm, or lessthan or equal to 7.5 nM, as measure by deposition of the complementmembrane attack complex.

An isolated antibody or antigen binding fragment thereof as describedherein can inhibit the alternative complement pathway with an IC50 ofless than or equal to 80 nM, less than or equal to 50 nM, less than orequal to 45 nM, or less than or equal to 35 nM, as measure by generationof C3a.

An isolated antibody or antigen binding fragment thereof as describedherein may also inhibit the alternative complement pathway with an IC50of less than or equal to 80 nM, less than or equal to 50 nM, less thanor equal to 45 nM, or less than or equal to 35 nM, as measure bygeneration of iC3b.

An isolated antibody or antigen binding fragment thereof as describedherein may also inhibit the alternative complement pathway with an IC50of less than or equal to 80 nM, less than or equal to 50 nM, less thanor equal to 45 nM, or less than or equal to 35 nM, as measure bygeneration of C5a.

An isolated antibody or antigen binding fragment thereof as describedherein may also inhibit the alternative complement pathway with an IC50of less than or equal to 80 nM, less than or equal to 50 nM, less thanor equal to 45 nM, or less than or equal to 35 nM, as measure bygeneration of C5b.

An isolated antibody or antigen binding fragment thereof as describedherein may also inhibit the alternative complement pathway bydestabilizing and/or blocking the activity of C3 and/or C5 convertase,as measured by a decrease in production of C3a, C3b, iC3b, C5a, and/orC5b.

An isolated antibody or antigen binding fragment thereof as describedherein may also inhibit the generation of C5a with an IC50 of less thanor equal to 80 nM, less than or equal to 50 nM, less than or equal to 45nM, or less than or equal to 35 nM.

The isolated antibodies, or antigen binding fragment thereof, may alsoblock Factor P binding to C3b and/or prevent Factor P binding to thecell surface or to DNA or oligonucleotides.

Another aspect of the invention includes an isolated antibody, orantigen binding fragment thereof, that specifically binds to human,cynomolgus, rat and/or rabbit Factor P. In a further aspect, theisolated antibody, or antigen binding fragment, competes for bindingwith an antibody, or antigen binding fragment, described in Table 1.

The isolated antibodies, or antigen binding fragments thereof, asdescribed herein can be a monoclonal antibodies, a human or humanizedantibodies, a chimeric antibodies, single chain antibodies, Fabfragments, Fv fragments, F(ab′)2 fragments, or ScFv fragments, and/orIgG isotypes.

The isolated antibodies, or antigen binding fragments thereof, asdescribed herein can also include a framework in which an amino acid hasbeen substituted into the antibody framework from the respective humanVH or VL germline sequences.

Another aspect of the invention includes an isolated antibody or antigenbinding fragment thereof having the heavy and light chain sequences ofFabs described in Table 1. For example, the isolated antibody or antigenbinding fragment thereof can have the heavy and light chain sequences ofFab NVS962, NVS963, NVS964, NVS965, NVS966, NVS967, NVS962-G, NVS962-S,NVS962-T, NVS962-Q, NVS962-S31A, NVS965-Q, NVS965-S, NVS965-T, NVS804,NVS805, NVS806, NVS807, or NVS808.

A further aspect of the invention includes an isolated antibody orantigen binding fragment thereof having the heavy and light chainvariable domain sequences of Fabs described in Table 1. For example, theisolated antibody or antigen binding fragment there of can have theheavy and light chain variable domain sequence of Fab NVS962, NVS963,NVS964, NVS965, NVS966, NVS967, NVS962-G, NVS962-S, NVS962-T, NVS962-Q,NVS962-S31A, NVS965-Q, NVS965-S, NVS965-T, NVS804, NVS805, NVS806,NVS807, or NVS808.

The invention also relates to an isolated antibody or antigen bindingfragment thereof that includes a heavy chain CDR1 selected from thegroup consisting of SEQ ID NOs 1, 15, 29, 43, 57, 71, 85, 99, 113, 127,141, 155, 169, 183, 197, 211, 225, 239, 253, and 267; a heavy chain CDR2selected from the group consisting of SEQ ID NOs: 2, 16, 30, 44, 58, 72,86, 100, 114, 128, 142, 156, 170, 184, 198, 212, 226, 240, 254, and 268;and a heavy chain CDR3 selected from the group consisting of SEQ ID NOs:3, 17, 31, 45, 59, 73, 87, 101, 115, 129, 143, 157, 171, 185, 199, 213,227, 241, 255, and 269, wherein the isolated antibody or antigen bindingfragment thereof binds to human Factor P. In another aspect, theisolated antibody or antigen binding fragment thereof further includes alight chain CDR1 selected from the group consisting of SEQ ID NOs: 4,18, 32, 46, 60, 74, 88, 102, 116, 130, 144, 158, 172, 186, 200, 214,228, 242, 256, and 270; a light chain CDR2 selected from the groupconsisting of SEQ ID NOs 5, 19, 33, 47, 61, 75, 89, 103, 117, 131, 145,159, 173, 187, 201, 215, 229, 243, 257, and 271; and a light chain CDR3selected from the group consisting of SEQ ID NOs 6, 20, 34, 48, 62, 76,90, 104, 118, 132, 146, 160, 174, 188, 202, 216, 230, 244, 258, and 272.

The invention also relates to an isolated antibody or antigen bindingfragment thereof that includes a light chain CDR1 selected from thegroup consisting of SEQ ID NOs: 4, 18, 32, 46, 60, 74, 88, 102, 116,130, 144, 158, 172, 186, 200, 214, 228, 242, 256, and 270; a light chainCDR2 selected from the group consisting of SEQ ID NOs 5, 19, 33, 47, 61,75, 89, 103, 117, 131, 145, 159, 173, 187, 201, 215, 229, 243, 257, and271; and a light chain CDR3 selected from the group consisting of SEQ IDNOs 6, 20, 34, 48, 62, 76, 90, 104, 118, 132, 146, 160, 174, 188, 202,216, 230, 244, 258, and 272, wherein the isolated antibody or antigenbinding fragment thereof binds to human Factor P.

The invention also relates to an isolated antibody or antigen bindingfragment thereof that binds Factor P having HCDR1, HCDR2, HCDR3 andLCDR1, LCDR2, LCDR3, wherein HCDR1, HCDR2, HCDR3 comprises SEQ ID NOs:1, 2, 3, and LCDR1, LCDR2, LCDR3 comprises SEQ ID NOs: 4, 5, 6; orHCDR1, HCDR2, HCDR3 and LCDR1, LCDR2, LCDR3, wherein HCDR1, HCDR2, HCDR3comprises SEQ ID NOs 15, 16, 17, and LCDR1, LCDR2, LCDR3 comprises SEQID NOs: 18, 19, 20; or HCDR1, HCDR2, HCDR3 and LCDR1, LCDR2, LCDR3,wherein HCDR1, HCDR2, HCDR3 comprises SEQ ID NOs 29, 30, 31, and LCDR1,LCDR2, LCDR3 comprises SEQ ID NOs: 32, 33, 34; or HCDR1, HCDR2, HCDR3and LCDR1, LCDR2, LCDR3, wherein HCDR1, HCDR2, HCDR3 comprises SEQ IDNOs 43, 44, 45, and LCDR1, LCDR2, LCDR3 comprises SEQ ID NOs: 46, 47,48; or HCDR1, HCDR2, HCDR3 and LCDR1, LCDR2, LCDR3, wherein HCDR1,HCDR2, HCDR3 comprises SEQ ID NOs 57, 58, 59, and LCDR1, LCDR2, LCDR3comprises SEQ ID NOs: 60, 61, 62; or HCDR1, HCDR2, HCDR3 and LCDR1,LCDR2, LCDR3, wherein HCDR1, HCDR2, HCDR3 comprises SEQ ID NOs 71, 72,73, and LCDR1, LCDR2, LCDR3 comprises SEQ ID NOs: 74, 75, 76; or HCDR1,HCDR2, HCDR3 and LCDR1, LCDR2, LCDR3, wherein HCDR1, HCDR2, HCDR3comprises SEQ ID NOs 85, 86, 87, and LCDR1, LCDR2, LCDR3 comprises SEQID NOs: 88, 89, 90; or HCDR1, HCDR2, HCDR3 and LCDR1, LCDR2, LCDR3,wherein HCDR1, HCDR2, HCDR3 comprises SEQ ID NOs 99, 100, 101, andLCDR1, LCDR2, LCDR3 comprises SEQ ID NOs: 102, 103, 104; or HCDR1,HCDR2, HCDR3 and LCDR1, LCDR2, LCDR3, wherein HCDR1, HCDR2, HCDR3comprises SEQ ID NOs 113, 114, 115, and LCDR1, LCDR2, LCDR3 comprisesSEQ ID NOs: 116, 117, 118; or HCDR1, HCDR2, HCDR3 and LCDR1, LCDR2,LCDR3, wherein HCDR1, HCDR2, HCDR3 comprises SEQ ID NOs 127, 128, 129,and LCDR1, LCDR2, LCDR3 comprises SEQ ID NOs: 130, 131, 132; or HCDR1,HCDR2, HCDR3 and LCDR1, LCDR2, LCDR3, wherein HCDR1, HCDR2, HCDR3comprises SEQ ID NOs 141, 142, 143, and LCDR1, LCDR2, LCDR3 comprisesSEQ ID NOs: 144, 145, 146; or HCDR1, HCDR2, HCDR3 and LCDR1, LCDR2,LCDR3, wherein HCDR1, HCDR2, HCDR3 comprises SEQ ID NOs 155, 156, 157,and LCDR1, LCDR2, LCDR3 comprises SEQ ID NOs: 158, 159, 160; or HCDR1,HCDR2, HCDR3 and LCDR1, LCDR2, LCDR3, wherein HCDR1, HCDR2, HCDR3comprises SEQ ID NOs 169, 170, 171, and LCDR1, LCDR2, LCDR3 comprisesSEQ ID NOs: 172, 173, 174; or HCDR1, HCDR2, HCDR3 and LCDR1, LCDR2,LCDR3, wherein HCDR1, HCDR2, HCDR3 comprises SEQ ID NOs 183, 184, 185,and LCDR1, LCDR2, LCDR3 comprises SEQ ID NOs: 186, 187, 188; or HCDR1,HCDR2, HCDR3 and LCDR1, LCDR2, LCDR3, wherein HCDR1, HCDR2, HCDR3comprises SEQ ID NOs 197, 198, 199, and LCDR1, LCDR2, LCDR3 comprisesSEQ ID NOs: 200, 201, 202; or HCDR1, HCDR2, HCDR3 and LCDR1, LCDR2,LCDR3, wherein HCDR1, HCDR2, HCDR3 comprises SEQ ID NOs 211, 212, 213,and LCDR1, LCDR2, LCDR3 comprises SEQ ID NOs: 214, 215, 216; or HCDR1,HCDR2, HCDR3 and LCDR1, LCDR2, LCDR3, wherein HCDR1, HCDR2, HCDR3comprises SEQ ID NOs 225, 226, 227, and LCDR1, LCDR2, LCDR3 comprisesSEQ ID NOs: 228, 229, 230; or HCDR1, HCDR2, HCDR3 and LCDR1, LCDR2,LCDR3, wherein HCDR1, HCDR2, HCDR3 comprises SEQ ID NOs 239, 240, 241,and LCDR1, LCDR2, LCDR3 comprises SEQ ID NOs: 242, 243, 244; or HCDR1,HCDR2, HCDR3 and LCDR1, LCDR2, LCDR3, wherein HCDR1, HCDR2, HCDR3comprises SEQ ID NOs 253, 254, 255, and LCDR1, LCDR2, LCDR3 comprisesSEQ ID NOs: 256, 257, 258; or HCDR1, HCDR2, HCDR3 and LCDR1, LCDR2,LCDR3, wherein HCDR1, HCDR2, HCDR3 comprises SEQ ID NOs 267, 268, 269,and LCDR1, LCDR2, LCDR3 comprises SEQ ID NOs: 270, 271, 272.

In one embodiment of the invention the isolated antibody or antigenbinding fragment thereof includes a heavy chain variable domain sequenceselected from the group consisting of SEQ ID NOs: 7, 21, 35, 49, 63, 77,91, 105, 119, 133, 147, 161, 175, 189, 203, 217, 231, 245, 259 and 273.In another embodiment, the isolated antibody or antigen binding fragmentfurther comprises a light chain variable domain sequence wherein theheavy chain variable domain and light chain variable domain combine toform and antigen binding site for Factor P. In a further embodiment theisolated antibody or antigen binding fragment further includes a lightchain variable domain sequence selected from SEQ ID NOs: 8, 22, 36, 50,64, 78, 92, 106, 120, 134, 148, 162, 176, 190, 204, 218, 232, 246, 260,and 274 wherein said isolated antibody or antigen binding fragmentthereof binds Factor P.

The invention also relates to an isolated antibody or antigen bindingfragment thereof that includes a light chain variable domain sequenceselected from the group consisting of SEQ ID NOs: 8, 22, 36, 50, 64, 78,92, 106, 120, 134, 148, 162, 176, 190, 204, 218, 232, 246, 260, and 274,wherein said isolated antibody or antigen binding fragment thereof bindsto human Factor P. In one embodiment, the isolated antibody or antigenbinding fragment further comprises a heavy chain variable domainsequence wherein the light chain variable domain and heavy chainvariable domain combine to form and antigen binding site for Factor P.

In another embodiment of the invention, the isolated antibody or antigenbinding fragment thereof that binds Factor P, may have heavy and lightchain variable domains comprising the sequences of SEQ ID NOs: 7 and 8;21 and 22; 35 and 36; 49 and 50; 63 and 64; 77 and 78; 91 and 92; 104and 105; 118 and 119; 132 and 133; 146 and 147; 160 and 161; 174 and175; 188 and 189; 202 and 203; 216 and 217; 230 and 231; 244 and 245;258 and 259; or 272 and 273, respectively.

The invention further relates to an isolated antibody or antigen bindingfragment thereof, that includes a heavy chain variable domain having atleast 90% sequence identity to a sequence selected from the groupconsisting of SEQ ID NOs: 7, 21, 35, 49, 63, 77, 91, 105, 119, 133, 147,161, 175, 189, 203, 217, 231, 245, 259 and 273, wherein said antibodybinds to Factor P. In one aspect, the isolated antibody or antigenbinding fragment thereof also includes a light chain variable domainhaving at least 95% sequence identity to a sequence selected from thegroup consisting of SEQ ID NOs 8, 22, 36, 50, 64, 78, 92, 106, 120, 134,148, 162, 176, 190, 204, 218, 232, 246, 260, and 274.

In another embodiment the isolated antibody or antigen binding fragmentthereof, may include a light chain variable domain having at least 90%sequence identity to a sequence selected from the group consisting ofSEQ ID NOs 8, 22, 36, 50, 64, 78, 92, 106, 120, 134, 148, 162, 176, 190,204, 218, 232, 246, 260, and 274, wherein said antibody binds Factor P.

In another embodiment the isolated antibody, or antigen binding fragmentthereof, that binds to Factor P may have a heavy chain comprising thesequence of SEQ ID NO: 9, 23, 37, 51, 65, 79, 93, 107, 121, 135, 149,163, 177, 191, 205, 219, 233, 247, 261 or 275. In a further embodiment,the isolated antibody also includes a light chain that can combine withthe heavy chain to form an antigen binding site to human Factor P. In afurther embodiment, the isolated antibody or antigen binding fragmentthereof includes a light chain having a sequence comprising SEQ ID NO:10, 24, 38, 52, 66, 80, 94, 108, 122, 136, 150, 164, 178, 192, 206, 220,234, 248, 262, or 276.

The invention still further relates to an isolated antibody or antigenbinding fragment thereof that includes a heavy chain having at least 90%sequence identity to a sequence selected from the group consisting ofSEQ ID NOs 9, 23, 37, 51, 65, 79, 93, 107, 121, 135, 149, 163, 177, 191,205, 219, 233, 247, 261 and 275, wherein said antibody binds to FactorP. In one aspect, the isolated antibody or antigen binding fragmentthereof also includes a light chain having at least 95% sequenceidentity to a sequence selected from the group consisting of SEQ ID NOs10, 24, 38, 52, 66, 80, 94, 108, 122, 136, 150, 164, 178, 192, 206, 220,234, 248, 262, and 276.

The invention still further relates to an isolated antibody or antigenbinding fragment thereof that includes a light chain having at least 90%sequence identity to a sequence selected from the group consisting ofSEQ ID NOs 9, 23, 37, 51, 65, 79, 93, 107, 121, 135, 149, 163, 177, 191,205, 219, 233, 247, 261 and 275, wherein said antibody binds Factor P.

The invention also relates to compositions comprising the isolatedantibody, or antigen binding fragment thereof, described herein. As wellas, antibody compositions in combination with a pharmaceuticallyacceptable carrier. Specifically, the invention further includespharmaceutical compositions comprising an antibody or antigen bindingfragment thereof of Table 1, such as, for example antibody NVS962,NVS963, NVS964, NVS965, NVS966, NVS967, NVS962-G, NVS962-S, NVS962-T,NVS962-Q, NVS962-S31A, NVS965-Q, NVS965-S, NVS965-T, NVS804, NVS805,NVS806, NVS807, or NVS808. The invention also relates to pharmaceuticalcompositions comprising a combination of two or more of the isolatedantibodies or antigen binding fragments thereof of Table 1.

The invention also relates to an isolated nucleic acid comprising asequence encoding a polypeptide that includes a heavy chain variabledomain having at least 90% sequence identity to a sequence selected fromthe group consisting of SEQ ID NOs: 7, 21, 35, 49, 63, 77, 91, 105, 119,133, 147, 161, 175, 189, 203, 217, 231, 245, 259 and 273.

The invention also relates to an isolated nucleic acid comprising asequence encoding a polypeptide that includes a light chain variabledomain having at least 90% sequence identity to a sequence selected fromthe group consisting of SEQ ID NOs 8, 22, 36, 50, 64, 78, 92, 106, 120,134, 148, 162, 176, 190, 204, 218, 232, 246, 260, and 274.

The invention also relates to a vector that includes one or more of thenucleic acid molecules described herein.

The invention also relates to an isolated host cell that includes arecombinant DNA sequence encoding a heavy chain of the antibodydescribed above, and a second recombinant DNA sequence encoding a lightchain of the antibody described above, wherein said DNA sequences areoperably linked to a promoter and are capable of being expressed in thehost cell. It is contemplated that the antibody can be a humanmonoclonal antibody. It is also contemplated that the host cell is anon-human mammalian cell.

The invention also relates to a method of inhibiting the complementmediated cell death wherein the method includes the step of contacting acell with an effective amount of a composition comprising the isolatedantibody or antigen binding fragments thereof described herein. It iscontemplated that the cell is a human cell. It is further contemplatedthat the cell is in a subject. It is still further contemplated that thesubject is human.

The invention still further relates to a method of inhibiting thealternative complement pathway in a cell wherein the method includes thestep of contacting the cell with an effective amount of a compositioncomprising the isolated antibody or antigen binding fragments thereofdescribed herein. In one aspect, it is contemplated that the cell is ahuman cell. It is further contemplated that the cell is in a subject. Itis still further contemplated that the subject is human.

The invention also relates to a method of inhibiting the formation ofmembrane attack complex in a cell wherein the method includes the stepof contacting the cell with an effective amount of a compositioncomprising the isolated antibody or antigen binding fragments thereofdescribed herein. It is contemplated that the cell is a human cell. Itis further contemplated that the cell is in a subject. It is stillfurther contemplated that the subject is human.

Any of the foregoing isolated antibodies or antigen binding fragmentsthereof may be a monoclonal antibody or antigen binding fragmentthereof.

In one aspect, the invention provides a first antibody, or antigenbinding fragment thereof, that binds Factor P, and a second antibody, orantigen binding fragment thereof, that binds C5, wherein saidcombination inhibits the alternative complement pathway. In one aspectthe first and second antibodies can be in combination as a composition.

Such a combination can be used to inhibit ocular inflammation. Ocularinflammation can be determined by measuring neutrophil accumulationand/or macrophage recruitment in the retina.

In one aspect, such a combination can be used to inhibit neutrophilaccumulation in the retina, or macrophage recruitment in the retina.

In one aspect, the antibody in such a combination that binds Factor P,binds a region of Factor P comprising SEQ ID NO: 408. Alternatively orin combination, such an antibody binds a region of Factor P comprisingSEQ ID NO: 407.

In a further aspect, the combination of antibodies or binding fragmentsthereof that bind Factor P and C5 include a first antibody or antigenbinding fragment selected from Table 1 and a second antibody orantigen-binding fragment selected from Table 2. In one aspect, the firstantibody, or antigen binding fragment thereof binds the same epitope asis an antibody described in Table 1 and the second antibody, or antigenbinding fragment thereof, binds the same epitope as is an antibodydescribed in Table 2.

In one aspect, the invention provides a first antibody, or antigenbinding fragment thereof that comprises a heavy chain CDR1, 2, 3, and alight chain CDR1, 2, 3, selected from the group consisting of a) a heavychain variable region HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs:1, 2, and 3, respectively, and light chain variable region LCDR1, LCDR2,and LCDR3 as set forth in SEQ ID NOs: 4, 5, and 6, respectively; b) aheavy chain variable region HCDR1, HCDR2 and HCDR3 as set forth in SEQID NOs: 15, 16, and 17, respectively, and light chain variable regionLCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NOs: 18, 19, and 20,respectively; c) a heavy chain variable region HCDR1, HCDR2 and HCDR3 asset forth in SEQ ID NOs: 29, 30, and 31, respectively, and light chainvariable region LCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NOs: 32,33, and 34, respectively; d) a heavy chain variable region HCDR1, HCDR2and HCDR3 as set forth in SEQ ID NOs: 43, 44, and 45, respectively, andlight chain variable region LCDR1, LCDR2, and LCDR3 as set forth in SEQID NOs: 46, 47, and 48, respectively; e) a heavy chain variable regionHCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs: 57, 58, and 59,respectively, and light chain variable region LCDR1, LCDR2, and LCDR3 asset forth in SEQ ID NOs: 60, 61, and 62, respectively; f) a heavy chainvariable region HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs: 71,72, and 73, respectively, and light chain variable region LCDR1, LCDR2,and LCDR3 as set forth in SEQ ID NOs: 74, 75, and 76, respectively; g) aheavy chain variable region HCDR1, HCDR2 and HCDR3 as set forth in SEQID NOs: 85, 86, and 87, respectively, and light chain variable regionLCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NOs: 88, 89, and 90,respectively; h) a heavy chain variable region HCDR1, HCDR2 and HCDR3 asset forth in SEQ ID NOs: 99, 100, and 101, respectively, and light chainvariable region LCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NOs: 102,103, and 104, respectively; i) a heavy chain variable region HCDR1,HCDR2 and HCDR3 as set forth in SEQ ID NOs: 113, 114, and 115,respectively, and light chain variable region LCDR1, LCDR2, and LCDR3 asset forth in SEQ ID NOs: 116, 117, and 118, respectively; j) a heavychain variable region HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs:127, 128, and 129, respectively, and light chain variable region LCDR1,LCDR2, and LCDR3 as set forth in SEQ ID NOs: 130, 131, and 132,respectively; k) a heavy chain variable region HCDR1, HCDR2 and HCDR3 asset forth in SEQ ID NOs: 141, 142, and 143, respectively, and lightchain variable region LCDR1, LCDR2, and LCDR3 as set forth in SEQ IDNOs: 144, 145, and 146, respectively; I) a heavy chain variable regionHCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs: 155, 156, and 157,respectively, and light chain variable region LCDR1, LCDR2, and LCDR3 asset forth in SEQ ID NOs: 158, 159, and 160, respectively; m) a heavychain variable region HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs:169, 170, and 171, respectively, and light chain variable region LCDR1,LCDR2, and LCDR3 as set forth in SEQ ID NOs: 172, 173, and 174,respectively; n) a heavy chain variable region HCDR1, HCDR2 and HCDR3 asset forth in SEQ ID NOs: 183, 184, and 185, respectively, and lightchain variable region LCDR1, LCDR2, and LCDR3 as set forth in SEQ IDNOs: 186, 187, and 188, respectively; o) a heavy chain variable regionHCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs: 197, 198, and 199,respectively, and light chain variable region LCDR1, LCDR2, and LCDR3 asset forth in SEQ ID NOs: 200, 201, and 202, respectively; p) a heavychain variable region HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs:211, 212, and 213, respectively, and light chain variable region LCDR1,LCDR2, and LCDR3 as set forth in SEQ ID NOs: 214, 215, and 216,respectively; q) a heavy chain variable region HCDR1, HCDR2 and HCDR3 asset forth in SEQ ID NOs: 225, 226, and 227, respectively, and lightchain variable region LCDR1, LCDR2, and LCDR3 as set forth in SEQ IDNOs: 228, 229, and 230, respectively; r) a heavy chain variable regionHCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs: 239, 240, and 241,respectively, and light chain variable region LCDR1, LCDR2, and LCDR3 asset forth in SEQ ID NOs: 242, 243, and 244, respectively; s) a heavychain variable region HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs:253, 254, and 255, respectively, and light chain variable region LCDR1,LCDR2, and LCDR3 as set forth in SEQ ID NOs: 256, 257, and 258,respectively; and t) a heavy chain variable region HCDR1, HCDR2 andHCDR3 as set forth in SEQ ID NOs: 267, 268, and 269, respectively, andlight chain variable region LCDR1, LCDR2, and LCDR3 as set forth in SEQID NOs: 270, 271, and 272, respectively, and wherein the second antibodyor antigen binding fragment thereof comprises a heavy chain CDR1, 2, 3and light chain CDR1, 2, 3 selected from the group consisting of: a) aheavy chain variable region HCDR1, HCDR2 and HCDR3 as set forth in SEQID NOs: 410, 411, and 412, respectively, and light chain variable regionLCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NOs: 413, 414, and 415,respectively; b) a heavy chain variable region HCDR1, HCDR2 and HCDR3 asset forth in SEQ ID NOs: 426, 427, and 428, respectively, and lightchain variable region LCDR1, LCDR2, and LCDR3 as set forth in SEQ IDNOs: 429, 430, and 431, respectively; c) a heavy chain variable regionHCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs: 442, 443, and 444,respectively, and light chain variable region LCDR1, LCDR2, and LCDR3 asset forth in SEQ ID NOs: 445, 446, and 447, respectively; d) a heavychain variable region HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs:426, 458, and 428, respectively, and light chain variable region LCDR1,LCDR2, and LCDR3 as set forth in SEQ ID NOs: 429, 430, and 459,respectively; and e) a heavy chain variable region HCDR1, HCDR2 andHCDR3 as set forth in SEQ ID NOs: 470, 471, and 472, respectively, andlight chain variable region LCDR1, LCDR2, and LCDR3 as set forth in SEQID NOs: 473, 474 and 475, respectively.

In one aspect, the invention relates to a first and second antibody orantigen binding fragment thereof (which may be in combination as acomposition) where the first antibody or antigen binding fragmentthereof includes heavy and light chain variable regions having aminoacid sequences at least 90% identical to SEQ ID NOs: 7 and 8; SEQ IDNOs: 21 and 22; SEQ ID NOs: 35 and 36; SEQ ID NOs: 49 and 50; SEQ IDNOs: 63 and 64; SEQ ID NOs: 77 and 78; SEQ ID NOs: 91 and 92; SEQ IDNOs: 105 and 106; SEQ ID NOs: 119 and 120; SEQ ID NOs: 133 and 134; SEQID NOs: 147 and 148; SEQ ID NOs: 161 and 162; SEQ ID NOs: 175 and 176;SEQ ID NOs: 189 and 190; SEQ ID NOs: 203 and 204; SEQ ID NOs: 217 and218; SEQ ID NOs: 231 and 232; SEQ ID NOs: 245 and 246; SEQ ID NOs: 259and 260; or SEQ ID NOs: 273 and 274, respectively, and wherein thesecond antibody or antigen binding fragment thereof includes heavy andlight chain variable regions having amino acid sequences at least 90%identical to SEQ ID NOs: 416 and 417; SEQ ID NOs: 432 and 433; SEQ IDNOs: 448 and 449; SEQ ID NOs: 460 and 461; or SEQ ID NOs: 476 and 477,respectively.

In one aspect, the invention relates to a first and second antibody orantigen binding fragment thereof (which may be in combination as acomposition) where the first antibody or antigen binding fragmentthereof includes heavy and light chain variable regions having aminoacid sequences selected from SEQ ID NOs: 7 and 8; SEQ ID NOs: 21 and 22;SEQ ID NOs: 35 and 36; SEQ ID NOs: 49 and 50; SEQ ID NOs: 63 and 64; SEQID NOs: 77 and 78; SEQ ID NOs: 91 and 92; SEQ ID NOs: 105 and 106; SEQID NOs: 119 and 120; SEQ ID NOs: 133 and 134; SEQ ID NOs: 147 and 148;SEQ ID NOs: 161 and 162; SEQ ID NOs: 175 and 176; SEQ ID NOs: 189 and190; SEQ ID NOs: 203 and 204; SEQ ID NOs: 217 and 218; SEQ ID NOs: 231and 232; SEQ ID NOs: 245 and 246; SEQ ID NOs: 259 and 260; or SEQ IDNOs: 273 and 274, respectively, and wherein the second antibody orantigen binding fragment thereof includes heavy and light chain variableregions having amino acid sequences selected from SEQ ID NOs: 416 and417; SEQ ID NOs: 432 and 433; SEQ ID NOs: 448 and 449; SEQ ID NOs: 460and 461; or SEQ ID NOs: 476 and 477, respectively.

In a further aspect, the invention includes a first and second antibodyor antigen binding fragment thereof (which may be in combination as acomposition) in which (a) the first antibody, or antigen bindingfragment thereof includes a heavy chain variable region comprising SEQID NO: 7, 21, 35, 49, 63, 77, 91, 105, 119, 133, 147, 161, 175, 189,203, 217, 231, 245, 259, or 273 and further includes a light chainvariable region, wherein said heavy chain variable region and said lightchain variable region combine to form an antigen binding site to FactorP and (b) wherein the second antibody or antigen binding fragmentthereof includes a heavy chain variable region comprising SEQ ID NO:416, 432, 448, 460 or 476 and further includes a light chain variableregion, wherein said heavy chain variable region and said light chainvariable region combine to form an antigen binding site to C5. In afurther aspect, the first antibody or antigen binding fragment thereofincludes the light chain variable region sequence of SEQ ID NO: 8, 22,36, 50, 64, 78, 92, 106, 120, 134, 148, 162, 176, 190, 204, 218, 232,246, 260, or 274, and the second antibody or antigen binding fragmentthereof includes the light chain variable region sequence of SEQ ID NO:417, 433, 449, 461 or 477.

In a further aspect, the invention includes a first and second antibodyor antigen binding fragment thereof (which may be in combination as acomposition) in which (a) the first antibody or antigen binding fragmentthereof includes a light chain variable domain comprising SEQ ID NO: 8,22, 36, 50, 64, 78, 92, 106, 120, 134, 148, 162, 176, 190, 204, 218,232, 246, 260, or 274 and further includes a heavy chain variabledomain, wherein the light chain variable domain and the heavy chainvariable domain combine to form an antigen binding site to Factor P and(b) wherein the second antibody or antigen binding fragment thereofincludes a light chain variable region comprises a light chain variabledomain includes SEQ ID NO: 417, 433, 449, 461 or 477 and furthercomprises a heavy chain variable domain, wherein the light chainvariable domain and the heavy chain variable domain combine to form anantigen binding site to C5.

In one aspect, the invention includes a first and second antibody orantigen binding fragment thereof (which may be in combination as acomposition) in which (a) the first antibody, or antigen bindingfragment thereof includes a heavy chain of SEQ ID NO: 9, 23, 37, 51, 65,79, 93, 107, 121, 135, 149, 163, 177, 191, 205, 219, 233, 247, 261 or275 and further includes a light chain, wherein the heavy chain and thelight chain combine to form an antigen binding site to Factor P and (b)wherein the second antibody or antigen binding fragment thereof includesa heavy chain of SEQ ID NO: 418, 434, 450, 462, or 478 and furtherincludes a light chain, wherein the heavy chain and the light chaincombine to form an antigen binding site to C5. In a further aspect, thefirst antibody or antigen binding fragment thereof includes a lightchain of SEQ ID NO: 10, 24, 38, 52, 66, 80, 94, 108, 122, 136, 150, 164,178, 192, 206, 220, 234, 248, 262 or 276, and wherein the secondantibody or antigen binding fragment thereof includes a light chain ofSEQ ID NO: 419, 435, 451, 463, or 479.

In one aspect, the invention includes a first and second antibody orantigen binding fragment thereof (which may be in combination as acomposition) in which (a) the first antibody, or antigen bindingfragment thereof includes a light chain of SEQ ID NO: 10, 24, 38, 52,66, 80, 94, 108, 122, 136, 150, 164, 178, 192, 206, 220, 234, 248, 262or 276 and further includes a heavy chain, wherein the light chain andthe heavy chain combine to form an antigen binding site to Factor P and(b) wherein the second antibody or antigen binding fragment thereofincludes a light chain of SEQ ID NO: 419, 435, 451, 463, or 479 andfurther includes a heavy chain, wherein the light chain and the heavychain combine to form an antigen binding site to C5.

In one aspect, the invention includes a first and second antibody orantigen binding fragment thereof (which may be in combination as acomposition) wherein the first antibody, or antigen binding fragmentthereof includes a heavy chain with an amino acid sequence having atleast 90% sequence identity to SEQ ID NO: 9, 23, 37, 51, 65, 79, 93,107, 121, 135, 149, 163, 177, 191, 205, 219, 233, 247, 261 or 275 andfurther includes a light chain with an amino acid sequence having atleast 90% sequence identity to SEQ ID NO: 10, 24, 38, 52, 66, 80, 94,108, 122, 136, 150, 164, 178, 192, 206, 220, 234, 248, 262 or 276 andwherein the second antibody or antigen binding fragment thereof includesa heavy chain with an amino acid sequence having at least 90% sequenceidentity to SEQ ID NO: 418, 434, 450, 462, or 478 and further includes alight chain with an amino acid sequence having at least 90% sequenceidentity to SEQ ID NO: 419, 435, 451, 463, or 479.

In a further aspect, the invention includes a first and second antibodyor antigen binding fragment thereof (which may be in combination as acomposition) wherein the first antibody, or antigen binding fragmentthereof includes a heavy chain with an amino acid sequence selected fromSEQ ID NO: 9, 23, 37, 51, 65, 79, 93, 107, 121, 135, 149, 163, 177, 191,205, 219, 233, 247, 261 or 275 and further includes a light chain withan amino acid sequence selected from SEQ ID NO: 10, 24, 38, 52, 66, 80,94, 108, 122, 136, 150, 164, 178, 192, 206, 220, 234, 248, 262 or 276and wherein the second antibody or antigen binding fragment thereofincludes a heavy chain with an amino acid sequence selected from SEQ IDNO: 418, 434, 450, 462, or 478 and further includes a light chain withan amino acid sequence selected from SEQ ID NO: 419, 435, 451, 463, or479.

In a further aspect, the invention includes a first and second antibodyor antigen binding fragment thereof (which may be in combination as acomposition) wherein the first antibody, or antigen binding fragmentthereof includes a heavy chain and a light chain with an amino acidsequence having at least 90% sequence identity, respectively, to SEQ IDNO: 9 and 10, 23 and 24, 37 and 38, 51 and 52, 65 and 66, 79 and 80, 93and 94, 107 and 108, 121 and 122, 135 and 136, 149 and 150, 163 and 164,177 and 178, 191 and 192, 205 and 206, 219 and 220, 233 and 234, 247 and248, 261 and 262, or 275 and 276; and wherein the second antibody orantigen binding fragment thereof includes a heavy chain and a lightchain with an amino acid sequence having at least 90% sequence identity,respectively, to SEQ ID NOs: 418 and 419, 434 and 435; 450 and 451; 462and 463; or 478 and 479.

In a still further aspect, the invention includes a first and secondantibody or antigen binding fragment thereof (which may be incombination as a composition) wherein the first antibody, or antigenbinding fragment thereof includes a heavy chain and a light chain withan amino acid sequence, respectively, selected from SEQ ID NO: 9 and 10,23 and 24, 37 and 38, 51 and 52, 65 and 66, 79 and 80, 93 and 94, 107and 108, 121 and 122, 135 and 136, 149 and 150, 163 and 164, 177 and178, 191 and 192, 205 and 206, 219 and 220, 233 and 234, 247 and 248,261 and 262, or 275 and 276; and wherein the second antibody or antigenbinding fragment thereof includes a heavy chain and a light chain withan amino acid sequence, respectively, selected from SEQ ID NOs: 418 and419, 434 and 435; 450 and 451; 462 and 463; or 478 and 479.

The invention further relates to an isolated nucleic acid moleculecomprising a nucleotide sequence encoding the first and/or secondantibody or antigen binding fragment thereof as described herein. Such anucleic acid sequence can be included in a vector, which may, in turn beincluded in a host cell which, in one aspect, is capable of expressingsuch nucleic acid sequence.

The invention further relates to a method of treating age relatedmacular degeneration in a subject comprising administering to saidsubject, an effective amount of a first and second antibody or antigenbinding fragment thereof, either singly, or in combination as acomposition. The subject may be a human.

The invention further relates to a method of inhibiting the alternativecomplement pathway in a subject comprising administering to said subjectan effective amount of a first and second antibody or antigen bindingfragment thereof, either singly, or in combination as a composition. Thesubject may be a human.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A-1C Depict the Factor P binding site. FIG. 1A illustrates therelative position TSR5 domain of Factor P and the TSR5 sequencefragments: A, B, C and D. FIG. 1B shows the human TSR5 sequence alignedwith the mouse sequence. Brackets indicate the sequence fragments ofTSR5. FIG. 1C illustrates the antibodies bind to region B of TSR5.

FIG. 2 shows the results of a hemolytic assay demonstrating inhibitionof the alternative complement pathway in 20% human serum.

FIG. 3 shows an isobologram generated using the data from the hemolyticassay depicted in FIG. 2.

FIG. 4 shows the % inhibition of macrophage infiltrates in a mousepoly-IC model, comparing the inhibition of anti-FactorP and anti-C5antibodies singly and in combination.

FIG. 5 shows an isobologram generated using the data from the poly-ICresults depicted in FIG. 4.

DETAILED DESCRIPTION

The present invention is based, in part, on the discovery of antibodymolecules that specifically bind to both human and cynomolgus Factor P.The invention relates to both full IgG format antibodies as well asantigen binding fragments thereof, such as Fab fragments (e.g., seeantibodies NVS965-S, NVS962-S, NVS804 and NVS807).

Accordingly, the present invention provides antibodies that specificallybind to Factor P (e.g., human Factor P, cynomolgus Factor P, rat FactorP, rabbit Factor P), pharmaceutical compositions, production methods,and methods of use of such antibodies and compositions.

DEFINITIONS

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by those of ordinary skillin the art to which this invention pertains.

The term “antibody” as used herein means a whole antibodies and anyantigen binding fragment (i. e., “antigen-binding portion”) or singlechains thereof. A whole antibody is a glycoprotein comprising at leasttwo heavy (H) chains and two light (L) chains inter-connected bydisulfide bonds. Each heavy chain is comprised of a heavy chain variableregion (abbreviated herein as VH) and a heavy chain constant region. Theheavy chain constant region is comprised of three domains, CH1, CH2 andCH3. Each light chain is comprised of a light chain variable region(abbreviated herein as VL) and a light chain constant region. The lightchain constant region is comprised of one domain, CL. The VH and VLregions can be further subdivided into regions of hypervariability,termed complementarity determining regions (CDR), interspersed withregions that are more conserved, termed framework regions (FR). Each VHand VL is composed of three CDRs and four FRs arranged fromamino-terminus to carboxy-terminus in the following order: FR1, CDR1,FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and lightchains contain a binding domain that interacts with an antigen. Theconstant regions of the antibodies may mediate the binding of theimmunoglobulin to host tissues or factors, including various cells ofthe immune system (e.g., effector cells) and the first component (C1q)of the classical complement system.

The term “antigen binding portion” or “antigen binding fragment” of anantibody, as used herein, refers to one or more fragments of an intactantibody that retain the ability to specifically bind to a given antigen(e.g., Factor P). Antigen binding functions of an antibody can beperformed by fragments of an intact antibody. Examples of bindingfragments encompassed within the term antigen binding portion or antigenbinding fragment of an antibody include a Fab fragment, a monovalentfragment consisting of the VL, VH, CL and CH1 domains; a F(ab)₂fragment, a bivalent fragment comprising two Fab fragments linked by adisulfide bridge at the hinge region; an Fd fragment consisting of theVH and CH1 domains; an Fv fragment consisting of the VL and VH domainsof a single arm of an antibody; a single domain antibody (dAb) fragment(Ward et al., 1989 Nature 341:544-546), which consists of a VH domain ora VL domain; and an isolated complementarity determining region (CDR).

Furthermore, although the two domains of the Fv fragment, VL and VH, arecoded for by separate genes, they can be joined, using recombinantmethods, by an artificial peptide linker that enables them to be made asa single protein chain in which the VL and VH regions pair to formmonovalent molecules (known as single chain Fv (scFv); see, e.g., Birdet al., 1988 Science 242:423-426; and Huston et al., 1988 Proc. Natl.Acad. Sci. 85:5879-5883). Such single chain antibodies include one ormore antigen binding portions or fragments of an antibody. Theseantibody fragments are obtained using conventional techniques known tothose of skill in the art, and the fragments are screened for utility inthe same manner as are intact antibodies.

Antigen binding fragments can also be incorporated into single domainantibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies,tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, 2005,Nature Biotechnology, 23, 9, 1126-1136). Antigen binding portions ofantibodies can be grafted into scaffolds based on polypeptides such asFibronectin type III (Fn3) (see U.S. Pat. No. 6,703,199, which describesfibronectin polypeptide monobodies).

Antigen binding fragments can be incorporated into single chainmolecules comprising a pair of tandem Fv segments (VH-CH1-VH-CH1) which,together with complementary light chain polypeptides, form a pair ofantigen binding regions (Zapata et al., 1995 Protein Eng.8(10):1057-1062; and U.S. Pat. No. 5,641,870).

As used herein, the term “affinity” refers to the strength ofinteraction between antibody and antigen at single antigenic sites.Within each antigenic site, the variable region of the antibody “arm”interacts through weak non-covalent forces with antigen at numeroussites; the more interactions, the stronger the affinity. As used herein,the term “high affinity” for an IgG antibody or fragment thereof (e.g.,a Fab fragment) refers to an antibody having a KD of 10⁻⁸ M or less,10⁻⁹ M or less, or 10⁻¹⁰ M, or 10⁻¹¹ M or less, or 10⁻¹² M or less, or10⁻¹³ M or less for a target antigen. However, high affinity binding canvary for other antibody isotypes. For example, high affinity binding foran IgM isotype refers to an antibody having a KD of 10⁻⁷ M or less, or10⁻⁸ M or less.

The term “amino acid” refers to naturally occurring and synthetic aminoacids, as well as amino acid analogs and amino acid mimetics thatfunction in a manner similar to the naturally occurring amino acids.Naturally occurring amino acids are those encoded by the genetic code,as well as those amino acids that are later modified, e.g.,hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acidanalogs refer to compounds that have the same basic chemical structureas a naturally occurring amino acid, i.e., an alpha carbon that is boundto a hydrogen, a carboxyl group, an amino group, and an R group, e.g.,homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium. Such analogs have modified R groups (e.g., norleucine) ormodified peptide backbones, but retain the same basic chemical structureas a naturally occurring amino acid. Amino acid mimetics refers tochemical compounds that have a structure that is different from thegeneral chemical structure of an amino acid, but that functions in amanner similar to a naturally occurring amino acid.

The term “binding specificity” as used herein refers to the ability ofan individual antibody combining site to react with only one antigenicdeterminant.

The phrase “specifically (or selectively) binds” to an antibody (e.g., aFactor P-binding antibody) refers to a binding reaction that isdeterminative of the presence of a cognate antigen (e.g., a human FactorP or cynomolgus Factor P) in a heterogeneous population of proteins andother biologics. The phrases “an antibody recognizing an antigen” and“an antibody specific for an antigen” are used interchangeably hereinwith the term “an antibody which binds specifically to an antigen”.

The term “conditions or disorders associated with macular degeneration”refers to any of a number of conditions in which the retinal maculadegenerates or becomes dysfunctional, e.g., as a consequence ofdecreased growth of cells of the macula, increased death orrearrangement of the cells of the macula (e.g., RPE cells), loss ofnormal biological function, or a combination of these events. Maculardegeneration results in the loss of integrity of the histoarchitectureof the cells and/or extracellular matrix of the normal macula and/or theloss of function of the cells of the macula. Examples of maculardegeneration-related disorder include AMD, North Carolina maculardystrophy, Sorsby's fundus dystrophy, Stargardt's disease, patterndystrophy, Best disease, dominant drusen, and malattia leventinese(radial drusen). The term also encompasses extramacular changes thatoccur prior to, or following dysfunction and/or degeneration of themacula. Thus, the term “macular degeneration-related disorder” alsobroadly includes any condition which alters or damages the integrity orfunction of the macula (e.g., damage to the RPE or Bruch's membrane).For example, the term encompasses retinal detachment, chorioretinaldegenerations, retinal degenerations, photoreceptor degenerations, RPEdegenerations, mucopolysaccharidoses, rod-cone dystrophies, cone-roddystrophies and cone degenerations.

The term “complement component”, “complement proteins” or “complementcomponent proteins” refers to the molecules that are involved inactivation of the complement system. The classical pathway componentsinclude, e.g., C1q, C1r, C1s, C4, C2, C3, C5, C6, C7, C8, C9, and C5b-9complex (membrane attack complex: MAC). The alternative pathwaycomponents include, e.g., Factor B, Factor D, Factor H, Factor I andProperdin.

The term “cellular activities regulated by the complement pathway”include cell damage resulting from the C5b-9 attack complex, vascularpermeability changes, contraction and migration of smooth muscle cells,T cell proliferation, immune adherence, aggregation of dendritic cells,monocytes, granulocyte and platelet, phagocytosis, migration andactivation of neutrophils (PMN) and macrophages.

Further, activation of the complement pathways results in the increaseof proinflammatory response contributed by the by-products within thecomplement pathway. Disorders associated with activation of thecomplement pathway include nephritis, asthma, reperfusion injury,hemodialysis, rheumatoid arthritis, systemic lupus, psoriasis, multiplesclerosis, transplantation, Alzheimer's disease, aHUS, MPGN II, or anyother complement-mediated disease. Disorders associated with maculardegeneration include AMD, North Carolina macular dystrophy, Sorsby'sfundus dystrophy, Stargardt's disease, pattern dystrophy, Best disease,dominant drusen, and malattia leventinese (radial drusen), extramacularchanges that occur prior to, or following dysfunction and/ordegeneration of the macula, retinal detachment, chorioretinaldegenerations, retinal degenerations, photoreceptor degenerations, RPEdegenerations, mucopolysaccharidoses, rod-cone dystrophies, cone-roddystrophies and cone degenerations.

The term “chimeric antibody” is an antibody molecule in which (a) theconstant region, or a portion thereof, is altered, replaced or exchangedso that the antigen binding site (variable region) is linked to aconstant region of a different or altered class, effector functionand/or species, or an entirely different molecule which confers newproperties to the chimeric antibody, e.g., an enzyme, toxin, hormone,growth factor, drug, etc.; or (b) the variable region, or a portionthereof, is altered, replaced or exchanged with a variable region havinga different or altered antigen specificity. For example, a mouseantibody can be modified by replacing its constant region with theconstant region from a human immunoglobulin. Due to the replacement witha human constant region, the chimeric antibody can retain itsspecificity in recognizing the antigen while having reduced antigenicityin human as compared to the original mouse antibody.

The term “Factor P protein” or “Factor P antigen” or “Factor P” are usedinterchangeably, and refers to the Factor P protein in differentspecies. For example, human Factor P has the sequence as set out inTable 1: SEQ ID NO: 401. Human Factor P can be obtained from ComplementTech, Tyler, Tex. Cynomolgus Factor P can be purified from cynomolgusserum (protocol adapted from Nakano et al., (1986) J Immunol Methods90:77-83). Examples of Factor P protein from other species are providedin Table 1, SEQ ID NOs: 402, 403, 404 or 405, as well as Factor Pprotein binding domains and fragments (e.g.: SEQ ID NOs: 406, 407 or408). Factor P is also know in the art as “Properdin”.

The term “conservatively modified variant” applies to both amino acidand nucleic acid sequences. With respect to particular nucleic acidsequences, conservatively modified variants refers to those nucleicacids which encode identical or essentially identical amino acidsequences, or where the nucleic acid does not encode an amino acidsequence, to essentially identical sequences. Because of the degeneracyof the genetic code, a large number of functionally identical nucleicacids encode any given protein. For instance, the codons GCA, GCC, GCGand GCU all encode the amino acid alanine. Thus, at every position wherean alanine is specified by a codon, the codon can be altered to any ofthe corresponding codons described without altering the encodedpolypeptide. Such nucleic acid variations are “silent variations,” whichare one species of conservatively modified variations. Every nucleicacid sequence herein which encodes a polypeptide also describes everypossible silent variation of the nucleic acid. One of skill willrecognize that each codon in a nucleic acid (except AUG, which isordinarily the only codon for methionine, and TGG, which is ordinarilythe only codon for tryptophan) can be modified to yield a functionallyidentical molecule. Accordingly, each silent variation of a nucleic acidthat encodes a polypeptide is implicit in each described sequence.

For polypeptide sequences, “conservatively modified variants” includeindividual substitutions, deletions or additions to a polypeptidesequence which result in the substitution of an amino acid with achemically similar amino acid. Conservative substitution tablesproviding functionally similar amino acids are well known in the art.Such conservatively modified variants are in addition to and do notexclude polymorphic variants, interspecies homologs, and alleles of theinvention. The following eight groups contain amino acids that areconservative substitutions for one another: 1) Alanine (A), Glycine (G);2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine(Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L),Methionine (M), Valine (V); 6) Phenylalanine (F), Tyrosine (Y),Tryptophan (W); 7) Serine (S), Threonine (T); and 8) Cysteine (C),Methionine (M) (see, e.g., Creighton, Proteins (1984)). In someembodiments, the term “conservative sequence modifications” are used torefer to amino acid modifications that do not significantly affect oralter the binding characteristics of the antibody containing the aminoacid sequence.

The term “epitope” means a protein determinant capable of specificbinding to an antibody. Epitopes usually consist of chemically activesurface groupings of molecules such as amino acids or sugar side chainsand usually have specific three dimensional structural characteristics,as well as specific charge characteristics. Conformational andnonconformational epitopes are distinguished in that the binding to theformer but not the latter is lost in the presence of denaturingsolvents.

The term “human antibody”, as used herein, is intended to includeantibodies having variable regions in which both the framework and CDRregions are derived from sequences of human origin. Furthermore, if theantibody contains a constant region, the constant region also is derivedfrom such human sequences, e.g., human germline sequences, or mutatedversions of human germline sequences. The human antibodies of theinvention may include amino acid residues not encoded by human sequences(e.g., mutations introduced by random or site-specific mutagenesis invitro or by somatic mutation in vivo).

The term “human monoclonal antibody” refers to antibodies displaying asingle binding specificity which have variable regions in which both theframework and CDR regions are derived from human sequences. In oneembodiment, the human monoclonal antibodies are produced by a hybridomawhich includes a B cell obtained from a transgenic nonhuman animal,e.g., a transgenic mouse, having a genome comprising a human heavy chaintransgene and a light chain transgene fused to an immortalized cell.

A “humanized” antibody is an antibody that retains the reactivity of anon-human antibody while being less immunogenic in humans. This can beachieved, for instance, by retaining the non-human CDR regions andreplacing the remaining parts of the antibody with their humancounterparts (i.e., the constant region as well as the frameworkportions of the variable region). See, e.g., Morrison et al., Proc.Natl. Acad. Sci. USA, 81:6851-6855, 1984; Morrison and Oi, Adv.Immunol., 44:65-92, 1988; Verhoeyen et al., Science, 239:1534-1536,1988; Padlan, Molec. Immun., 28:489-498, 1991; and Padlan, Molec.Immun., 31:169-217, 1994. Other examples of human engineering technologyinclude, but are not limited to Xoma technology disclosed in U.S. Pat.No. 5,766,886.

The terms “identical” or percent “identity,” in the context of two ormore nucleic acids or polypeptide sequences, refer to two or moresequences or subsequences that are the same. Two sequences are“substantially identical” if two sequences have a specified percentageof amino acid residues or nucleotides that are the same (i.e., 60%identity, optionally 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identityover a specified region, or, when not specified, over the entiresequence), when compared and aligned for maximum correspondence over acomparison window, or designated region as measured using one of thefollowing sequence comparison algorithms or by manual alignment andvisual inspection. Optionally, the identity exists over a region that isat least about 50 nucleotides (or 10 amino acids) in length, or morepreferably over a region that is 100 to 500 or 1000 or more nucleotides(or 20, 50, 200 or more amino acids) in length.

For sequence comparison, typically one sequence acts as a referencesequence, to which test sequences are compared. When using a sequencecomparison algorithm, test and reference sequences are entered into acomputer, subsequence coordinates are designated, if necessary, andsequence algorithm program parameters are designated. Default programparameters can be used, or alternative parameters can be designated. Thesequence comparison algorithm then calculates the percent sequenceidentities for the test sequences relative to the reference sequence,based on the program parameters.

A “comparison window”, as used herein, includes reference to a segmentof any one of the number of contiguous positions selected from the groupconsisting of from 20 to 600, usually about 50 to about 200, moreusually about 100 to about 150 in which a sequence may be compared to areference sequence of the same number of contiguous positions after thetwo sequences are optimally aligned. Methods of alignment of sequencesfor comparison are well known in the art. Optimal alignment of sequencesfor comparison can be conducted, e.g., by the local homology algorithmof Smith and Waterman (1970) Adv. Appl. Math. 2:482c, by the homologyalignment algorithm of Needleman and Wunsch, J. Mol. Biol. 48:443, 1970,by the search for similarity method of Pearson and Lipman, Proc. Nat'l.Acad. Sci. USA 85:2444, 1988, by computerized implementations of thesealgorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin GeneticsSoftware Package, Genetics Computer Group, 575 Science Dr., Madison,Wis.), or by manual alignment and visual inspection (see, e.g., Brent etal., Current Protocols in Molecular Biology, John Wiley & Sons, Inc.(Ringbou ed., 2003)).

Two examples of algorithms that are suitable for determining percentsequence identity and sequence similarity are the BLAST and BLAST 2.0algorithms, which are described in Altschul et al., Nuc. Acids Res.25:3389-3402, 1977; and Altschul et al., J. Mol. Biol. 215:403-410,1990, respectively. Software for performing BLAST analyses is publiclyavailable through the National Center for Biotechnology Information.This algorithm involves first identifying high scoring sequence pairs(HSPs) by identifying short words of length W in the query sequence,which either match or satisfy some positive-valued threshold score Twhen aligned with a word of the same length in a database sequence. T isreferred to as the neighborhood word score threshold (Altschul et al.,supra). These initial neighborhood word hits act as seeds for initiatingsearches to find longer HSPs containing them. The word hits are extendedin both directions along each sequence for as far as the cumulativealignment score can be increased. Cumulative scores are calculatedusing, for nucleotide sequences, the parameters M (reward score for apair of matching residues; always >0) and N (penalty score formismatching residues; always <0). For amino acid sequences, a scoringmatrix is used to calculate the cumulative score. Extension of the wordhits in each direction are halted when: the cumulative alignment scorefalls off by the quantity X from its maximum achieved value; thecumulative score goes to zero or below, due to the accumulation of oneor more negative-scoring residue alignments; or the end of eithersequence is reached. The BLAST algorithm parameters W, T, and Xdetermine the sensitivity and speed of the alignment. The BLASTN program(for nucleotide sequences) uses as defaults a wordlength (W) of 11, anexpectation (E) or 10, M=5, N=−4 and a comparison of both strands. Foramino acid sequences, the BLASTP program uses as defaults a wordlengthof 3, and expectation (E) of 10, and the BLOSUM62 scoring matrix (seeHenikoff and Henikoff, Proc. Natl. Acad. Sci. USA 89:10915, 1989)alignments (B) of 50, expectation (E) of 10, M=5, N=−4, and a comparisonof both strands.

The BLAST algorithm also performs a statistical analysis of thesimilarity between two sequences (see, e.g., Karlin and Altschul, Proc.Natl. Acad. Sci. USA 90:5873-5787, 1993). One measure of similarityprovided by the BLAST algorithm is the smallest sum probability (P(N)),which provides an indication of the probability by which a match betweentwo nucleotide or amino acid sequences would occur by chance. Forexample, a nucleic acid is considered similar to a reference sequence ifthe smallest sum probability in a comparison of the test nucleic acid tothe reference nucleic acid is less than about 0.2, more preferably lessthan about 0.01, and most preferably less than about 0.001.

The percent identity between two amino acid sequences can also bedetermined using the algorithm of E. Meyers and W. Miller (Comput. Appl.Biosci., 4:11-17, 1988) which has been incorporated into the ALIGNprogram (version 2.0), using a PAM120 weight residue table, a gap lengthpenalty of 12 and a gap penalty of 4. In addition, the percent identitybetween two amino acid sequences can be determined using the Needlemanand Wunsch (J. Mol, Biol. 48:444-453, 1970) algorithm which has beenincorporated into the GAP program in the GCG software package (availableon the world wide web at gcg.com), using either a Blossom 62 matrix or aPAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and alength weight of 1, 2, 3, 4, 5, or 6.

Other than percentage of sequence identity noted above, anotherindication that two nucleic acid sequences or polypeptides aresubstantially identical is that the polypeptide encoded by the firstnucleic acid is immunologically cross reactive with the antibodiesraised against the polypeptide encoded by the second nucleic acid, asdescribed below. Thus, a polypeptide is typically substantiallyidentical to a second polypeptide, for example, where the two peptidesdiffer only by conservative substitutions. Another indication that twonucleic acid sequences are substantially identical is that the twomolecules or their complements hybridize to each other under stringentconditions, as described below. Yet another indication that two nucleicacid sequences are substantially identical is that the same primers canbe used to amplify the sequence.

The term “inhibit (or inhibits) the alternative complement pathway”refers to the ability of Factor P antibodies to interfere withactivation of the alternative complement pathway. Specifically,“inhibit” refers to a statistically significant decrease (i.e., p<0.05)in alternative complement activation as measured by one or more assaysas described herein, including MAC formation, hemolytic assay, or C3bdeposition assay in a cell or subject following contact with ananti-Factor P antibody or fragment thereof as described herein relativeto a control. As used herein, “inhibit (or inhibits) the alternativecomplement pathway” can also refer to a clinically relevant improvementin visual function or retinal anatomy following treatment with ananti-Factor P antibody described herein in a patient diagnosed with agerelated macular degeneration as described below.

The term “isolated antibody” refers to an antibody that is substantiallyfree of other antibodies having different antigenic specificities (e.g.,an isolated antibody that specifically binds Factor P is substantiallyfree of antibodies that specifically bind antigens other than Factor P).An isolated antibody that specifically binds Factor P may, however, havecross-reactivity to other antigens. Moreover, an isolated antibody maybe substantially free of other cellular material and/or chemicals.

The term “isotype” refers to the antibody class (e.g., IgM, IgE, IgGsuch as IgG1 or IgG4) that is provided by the heavy chain constantregion genes. Isotype also includes modified versions of one of theseclasses, where modifications have been made to alter the Fc function,for example, to enhance or reduce effector functions or binding to Fcreceptors.

The term “Kassoc” or “Ka”, as used herein, is intended to refer to theassociation rate of a particular antibody-antigen interaction, whereasthe term “Kdis” or “Kd,” as used herein, is intended to refer to thedissociation rate of a particular antibody-antigen interaction. The term“K_(D)”, as used herein, is intended to refer to the dissociationconstant, which is obtained from the ratio of Kd to Ka (i.e. Kd/Ka) andis expressed as a molar concentration (M). K_(D) values for antibodiescan be determined using methods well established in the art. Methods fordetermining the K_(D) of an antibody include measuring surface plasmonresonance using a biosensor system such as a Biacore® system, ormeasuring affinity in solution by solution equilibrium titration (SET).

The terms “monoclonal antibody” or “monoclonal antibody composition” asused herein refer to a preparation of antibody molecules of singlemolecular composition. A monoclonal antibody composition displays asingle binding specificity and affinity for a particular epitope.

The term “nucleic acid” is used herein interchangeably with the term“polynucleotide” and refers to deoxyribonucleotides or ribonucleotidesand polymers thereof in either single- or double-stranded form. The termencompasses nucleic acids containing known nucleotide analogs ormodified backbone residues or linkages, which are synthetic, naturallyoccurring, and non-naturally occurring, which have similar bindingproperties as the reference nucleic acid, and which are metabolized in amanner similar to the reference nucleotides. Examples of such analogsinclude, without limitation, phosphorothioates, phosphoramidates, methylphosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides,peptide-nucleic acids (PNAs).

Unless otherwise indicated, a particular nucleic acid sequence alsoimplicitly encompasses conservatively modified variants thereof (e.g.,degenerate codon substitutions) and complementary sequences, as well asthe sequence explicitly indicated. Specifically, as detailed below,degenerate codon substitutions may be achieved by generating sequencesin which the third position of one or more selected (or all) codons issubstituted with mixed-base and/or deoxyinosine residues (Batzer et al.,Nucleic Acid Res. 19:5081, 1991; Ohtsuka et al., J. Biol. Chem.260:2605-2608, 1985; and Rossolini et al., Mol. Cell. Probes 8:91-98,1994).

The term “operably linked” refers to a functional relationship betweentwo or more polynucleotide (e.g., DNA) segments. Typically, the termrefers to the functional relationship of a transcriptional regulatorysequence to a transcribed sequence. For example, a promoter or enhancersequence is operably linked to a coding sequence if it stimulates ormodulates the transcription of the coding sequence in an appropriatehost cell or other expression system. Generally, promotertranscriptional regulatory sequences that are operably linked to atranscribed sequence are physically contiguous to the transcribedsequence, i.e., they are cis-acting. However, some transcriptionalregulatory sequences, such as enhancers, need not be physicallycontiguous or located in close proximity to the coding sequences whosetranscription they enhance.

As used herein, the term, “optimized” means that a nucleotide sequencehas been altered to encode an amino acid sequence using codons that arepreferred in the production cell or organism, generally a eukaryoticcell, for example, a cell of Pichia, a Chinese Hamster Ovary cell (CHO)or a human cell. The optimized nucleotide sequence is engineered toretain completely or as much as possible the amino acid sequenceoriginally encoded by the starting nucleotide sequence, which is alsoknown as the “parental” sequence. The optimized sequences herein havebeen engineered to have codons that are preferred in mammalian cells.However, optimized expression of these sequences in other eukaryoticcells or prokaryotic cells is also envisioned herein. The amino acidsequences encoded by optimized nucleotide sequences are also referred toas optimized.

The terms “polypeptide” and “protein” are used interchangeably herein torefer to a polymer of amino acid residues. The terms apply to amino acidpolymers in which one or more amino acid residue is an artificialchemical mimetic of a corresponding naturally occurring amino acid, aswell as to naturally occurring amino acid polymers and non-naturallyoccurring amino acid polymer. Unless otherwise indicated, a particularpolypeptide sequence also implicitly encompasses conservatively modifiedvariants thereof.

The term “recombinant human antibody”, as used herein, includes allhuman antibodies that are prepared, expressed, created or isolated byrecombinant means, such as antibodies isolated from an animal (e.g., amouse) that is transgenic or transchromosomal for human immunoglobulingenes or a hybridoma prepared therefrom, antibodies isolated from a hostcell transformed to express the human antibody, e.g., from atransfectoma, antibodies isolated from a recombinant, combinatorialhuman antibody library, and antibodies prepared, expressed, created orisolated by any other means that involve splicing of all or a portion ofa human immunoglobulin gene, sequences to other DNA sequences. Suchrecombinant human antibodies have variable regions in which theframework and CDR regions are derived from human germline immunoglobulinsequences. In certain embodiments, however, such recombinant humanantibodies can be subjected to in vitro mutagenesis (or, when an animaltransgenic for human Ig sequences is used, in vivo somatic mutagenesis)and thus the amino acid sequences of the VH and VL regions of therecombinant antibodies are sequences that, while derived from andrelated to human germline VH and VL sequences, may not naturally existwithin the human antibody germline repertoire in vivo.

The term “recombinant host cell” (or simply “host cell”) refers to acell into which a recombinant expression vector has been introduced. Itshould be understood that such terms are intended to refer not only tothe particular subject cell but to the progeny of such a cell. Becausecertain modifications may occur in succeeding generations due to eithermutation or environmental influences, such progeny may not, in fact, beidentical to the parent cell, but are still included within the scope ofthe term “host cell” as used herein.

The term “subject” includes human and non-human animals. Non-humananimals include all vertebrates (e.g.: mammals and non-mammals) such as,non-human primates (e.g.: cynomolgus monkey), sheep, dog, cow, chickens,amphibians, and reptiles. Except when noted, the terms “patient” or“subject” are used herein interchangeably. As used herein, the terms“cyno” or “cynomolgus” refer to the cynomolgus monkey (Macacafascicularis).

As used herein, the term “treating” or “treatment” of any disease ordisorder (i.e., AMD) refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment “treating” or “treatment” refers toalleviating or ameliorating at least one physical parameter includingthose which may not be discernible by the patient. In yet anotherembodiment, “treating” or “treatment” refers to modulating the diseaseor disorder, either physically, (e.g., stabilization of a discerniblesymptom), physiologically, (e.g., stabilization of a physicalparameter), or both. In yet another embodiment, “treating” or“treatment” refers to preventing or delaying the onset or development orprogression of the disease or disorder. “Prevention” as it relates toAMD means any action that prevents or slows a worsening in visualfunction, retinal anatomy, and/or an AMD disease parameter, as describedbelow, in a patient at risk for said worsening. More specifically,“treatment” of AMD means any action that results in the improvement orpreservation of visual function and/or reginal anatomy. Methods forassessing treatment and/or prevention of disease are known in the artand described hereinbelow.

The term “vector” is intended to refer to a polynucleotide moleculecapable of transporting another polynucleotide to which it has beenlinked. One type of vector is a “plasmid”, which refers to a circulardouble stranded DNA loop into which additional DNA segments may beligated. Another type of vector is a viral vector, such as anadeno-associated viral vector (AAV, or AAV2), wherein additional DNAsegments may be ligated into the viral genome. Certain vectors arecapable of autonomous replication in a host cell into which they areintroduced (e.g., bacterial vectors having a bacterial origin ofreplication and episomal mammalian vectors). Other vectors (e.g.,non-episomal mammalian vectors) can be integrated into the genome of ahost cell upon introduction into the host cell, and thereby arereplicated along with the host genome. Moreover, certain vectors arecapable of directing the expression of genes to which they areoperatively linked. Such vectors are referred to herein as “recombinantexpression vectors” (or simply, “expression vectors”). In general,expression vectors of utility in recombinant DNA techniques are often inthe form of plasmids. In the present specification, “plasmid” and“vector” may be used interchangeably as the plasmid is the most commonlyused form of vector. However, the invention is intended to include suchother forms of expression vectors, such as viral vectors (e.g.,replication defective retroviruses, adenoviruses and adeno-associatedviruses), which serve equivalent functions.

Factor P Antibodies & Antigen Binding Fragments

The present invention provides antibodies that specifically bind toFactor P. In some embodiments, the present invention provides antibodiesthat specifically bind to human, cynomolgus, rat and/or rabbit Factor P.Antibodies of the invention include, but are not limited to, the humanmonoclonal antibodies and Fabs, isolated as described in the Examples.

The present invention provides antibodies that specifically bind aFactor P protein (e.g., human and/or cynomolgus Factor P), wherein theantibodies comprise a VH domain having an amino acid sequence of SEQ IDNO: 7, 21, 35, 49, 63, 77, 91, 105, 119, 133, 147, 161, 175, 189, 203,217, 231, 245, 259 or 273. The present invention also providesantibodies that specifically bind to a Factor P protein, wherein theantibodies comprise a VH CDR having an amino acid sequence of any one ofthe VH CDRs listed in Table 1, infra. In particular, the inventionprovides antibodies that specifically bind to a Factor P protein (e.g.,human and/or cynomolgus Factor P), wherein the antibodies comprise (oralternatively, consist of) one, two, three, or more VH CDRs having anamino acid sequence of any of the VH CDRs listed in Table 1, infra.

The present invention provides antibodies that specifically bind to aFactor P protein, said antibodies comprising a VL domain having an aminoacid sequence of SEQ ID NO: 8, 22, 36, 50, 64, 78, 92, 106, 120, 134,148, 162, 176, 190, 204, 218, 232, 246, 260, or 274. The presentinvention also provides antibodies that specifically bind to a Factor Pprotein (e.g., human and/or cynomolgus Factor P), said antibodiescomprising a VL CDR having an amino acid sequence of any one of the VLCDRs listed in Table 1, infra. In particular, the invention providesantibodies that specifically bind to a Factor P protein (e.g., humanand/or cynomolgus Factor P), said antibodies comprising (oralternatively, consisting of) one, two, three or more VL CDRs having anamino acid sequence of any of the VL CDRs listed in Table 1, infra.

Other antibodies of the invention include amino acids that have beenmutated, yet have at least 60, 70, 80, 85, 90 or 95 percent identity inthe CDR regions with the CDR regions depicted in the sequences describedin Table 1. In some embodiments, it includes mutant amino acid sequenceswherein no more than 1, 2, 3, 4 or 5 amino acids have been mutated inthe CDR regions when compared with the CDR regions depicted in thesequence described in Table 1.

The present invention also provides nucleic acid sequences that encodeVH, VL, the full length heavy chain, and the full length light chain ofthe antibodies that specifically bind to a Factor P protein (e.g., humanand/or cynomolgus Factor P). Such nucleic acid sequences can beoptimized for expression in mammalian cells (for example, Table 1 showsthe optimized nucleic acid sequences for the heavy chain and light chainof antibodies of the invention).

TABLE 1 Examples of Factor P Antibodies, Fabs and Factor P ProteinsAMINO ACID SEQUENCE OR POLYNUCLEOTIDE (PN)SEQUENCE IDENTIFIER (SEQ.ID.NO:) AND SEQUENCE NVS962 CDRH1 1/281SYAIS (Kabat)/GGTFNSY (Chothia) CDRH2 2/282RIIPIFGTANYAQKFQG (Kabat)/IPIFGT (Chothia) CDRH3 3/283HGGYSFDS (Kabat)/HGGYSFDS (Chothia) CDRL1 4/284SGDNLGSKYVD (Kabat)/DNLGSKY (Chothia) CDRL2 5/285SDNNRPS (Kabat)/SDN (Chothia) CDRL3 6/286QTYTSGNNYL (Kabat)/YTSGNNYL (Chothia) VH 7EVQLVQSGAEVKKPGSSVKVSCKASGGTFNSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYC ARHGGYSFDSWGQGTLVTVSSVL 8 SYELTQPPSVSVAPGQTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTSGNNY LVFGGGTKLTVLHEAVY CHAIN 9 EVQLVQSGAEVKKPGSSVKVSCKASGGTFNSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARHGGYSFDSWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC LIGHT CHAIN 10SYELTQPPSVSVAPGQTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTSGNNYLVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRS YSCQVTHEGSTVEKTVAPTECSPN ENCODING 11 SEQ.ID.NO: 7GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCAACAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACAGCTTCGATAGCTGGGGCCAGGGCACCCTG GTGACCGTGAGCTCAPN ENCODING 12 SEQ.ID.NO: 8AGCTACGAGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCCAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCGAGGACGAGGCCGACTACTACTGCCAGACCTACACCAGCGGCAACAACTACCTGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTA PN ENCODING 13 SEQ.ID.NO: 9GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCAACAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACAGCTTCGATAGCTGGGGCCAGGGCACCCTGGTGACCGTGAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT PN ENCODING 14 SEQ.ID.NO: 10AGCTACGAGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCCAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCGAGGACGAGGCCGACTACTACTGCCAGACCTACACCAGCGGCAACAACTACCTGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTG GCCCCTACAGAATGTTCANVS963 CDRH1 15/287 SYAIS (Kabat)/GGTFSSY (Chothia) CDRH2 16/288PINPYYGDAIYAQKFQG (Kabat)/NPYYGD (Chothia) CDRH3 17/289YYSDYMDY (Kabat)/YYSDYMDY (Chothia) CDRL1 18/290TGSSSNIGAGYDVH (Kabat)/SSSNIGAGYD (Chothia) CDRL2 19/291DNSHRPS (Kabat)/DNS (Chothia) CDRL3 20/292ASYDESAHS (Kabat)/YDESAHS (Chothia) VH 21EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGPINPYYGDAIYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYC ARYYSDYMDYWGQGTLVTVSSVL 22 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIHDNSHRPSGVPDRFSGSKSGTSASLAITGLQSEDEADYYCASYDES AHSVFGGGTKLTVLHEAVY CHAIN 23 EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGPINPYYGDAIYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARYYSDYMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC LIGHT CHAIN 24QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIHDNSHRPSGVPDRFSGSKSGTSASLAITGLQSEDEADYYCASYDESAHSVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS PN ENCODING 25 SEQ.ID.NO: 21GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTTAGCAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCAGGACAGGGCCTGGAATGGATGGGCCCCATCAACCCCTACTACGGCGACGCCATCTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGCGCCCGGTACTACAGCGACTACATGGACTACTGGGGCCAGGGCACCCTG GTGACCGTGAGCTCAPN ENCODING 26 SEQ.ID.NO: 22CAGTCAGTGCTGACCCAGCCTCCCTCTGTGTCTGGCGCCCCTGGCCAGAGAGTGACCATCAGCTGCACCGGCTCCAGCAGCAACATCGGAGCTGGATACGACGTGCACTGGTATCAGCAGCTGCCCGGCACAGCCCCTAAGCTGCTGATCCACGACAACAGCCACAGACCCAGCGGCGTGCCCGATAGATTCAGCGGCAGCAAGAGCGGCACCAGCGCCAGCCTGGCCATCACCGGCCTGCAGAGCGAGGACGAGGCCGACTACTACTGCGCCAGCTACGACGAGAGCGCCCACAGCGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTA PN ENCODING 27 SEQ.ID.NO: 23GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTTAGCAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCAGGACAGGGCCTGGAATGGATGGGCCCCATCAACCCCTACTACGGCGACGCCATCTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGCGCCCGGTACTACAGCGACTACATGGACTACTGGGGCCAGGGCACCCTGGTGACCGTGAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT PN ENCODING 28 SEQ.ID.NO: 24CAGTCAGTGCTGACCCAGCCTCCCTCTGTGTCTGGCGCCCCTGGCCAGAGAGTGACCATCAGCTGCACCGGCTCCAGCAGCAACATCGGAGCTGGATACGACGTGCACTGGTATCAGCAGCTGCCCGGCACAGCCCCTAAGCTGCTGATCCACGACAACAGCCACAGACCCAGCGGCGTGCCCGATAGATTCAGCGGCAGCAAGAGCGGCACCAGCGCCAGCCTGGCCATCACCGGCCTGCAGAGCGAGGACGAGGCCGACTACTACTGCGCCAGCTACGACGAGAGCGCCCACAGCGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA NVS964 CDRH1 29/293SHYMH (Kabat)/GYTFTSH (Chothia) CDRH2 30/294KINADLGDTNYAQKFQG (Kabat)/NADLGD (Chothia) CDRH3 31/295DGIEHGGHYYWGYLFDI (Kabat)/DGIEHGGHYYWGYLFDI (Chothia) CDRL1 32/296SGDSIREYYVH (Kabat)/DSIREYY (Chothia) CDRL2 33/297DDTNRPS (Kabat)/DDT (Chothia) CDRL3 34/298AAWDFSPAI (Kabat)/WDFSPAI (Chothia) VH 35EVQLVQSGAEVKKPGASVKVSCKASGYTFTSHYMHWVRQAPGQGLEWMGKINADLGDTNYAQKFQGRVTMTRDTSISTAYMELSSLRSEDTAVYYCARDGIEHGGHYYWGYLFDIWGQGTLVTVSS VL 36SYELTQPPSVSVAPGQTARISCSGDSIREYYVHWYQQKPGQAPVLVIGDDTNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCAAWDFSPAI VFGGGTKLTVL HEAVY CHAIN37 EVQLVQSGAEVKKPGASVKVSCKASGYTFTSHYMHWVRQAPGQGLEWMGKINADLGDTNYAQKFQGRVTMTRDTSISTAYMELSSLRSEDTAVYYCARDGIEHGGHYYWGYLFDIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC LIGHT CHAIN 38SYELTQPPSVSVAPGQTARISCSGDSIREYYVHWYQQKPGQAPVLVIGDDTNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCAAWDFSPAIVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSY SCQVTHEGSTVEKTVAPTECSPN ENCODING 39 SEQ.ID.NO: 35GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCTGGCGCCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCTACACCTTCACCAGCCACTACATGCACTGGGTGCGCCAGGCTCCAGGACAGGGCCTGGAATGGATGGGCAAGATCAACGCCGACCTGGGCGACACCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATGACCCGGGACACCAGCATCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGCGCCAGGGACGGCATCGAGCACGGCGGCCACTACTACTGGGGCTACCTGTTCGACATCTGGGGCCAGGGCACCCTGGTGACCGTGAGCTCA PN ENCODING 40 SEQ.ID.NO: 36AGCTACGAGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCCAGACCGCCAGAATCAGCTGCAGCGGCGACAGCATCCGGGAGTACTACGTGCACTGGTATCAGCAGAAGCCCGGCCAGGCTCCTGTGCTGGTGATCGGCGACGACACCAACAGACCCAGCGGCATCCCCGAGAGATTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCGAGGACGAGGCCGATTACTACTGCGCCGCCTGGGACTTCAGCCCTGCCATCGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTA PN ENCODING 41 SEQ.ID.NO: 37GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCTGGCGCCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCTACACCTTCACCAGCCACTACATGCACTGGGTGCGCCAGGCTCCAGGACAGGGCCTGGAATGGATGGGCAAGATCAACGCCGACCTGGGCGACACCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATGACCCGGGACACCAGCATCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGCGCCAGGGACGGCATCGAGCACGGCGGCCACTACTACTGGGGCTACCTGTTCGACATCTGGGGCCAGGGCACCCTGGTGACCGTGAGCTCAGCATCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTT GAGCCCAAATCTTGTPN ENCODING 42 SEQ.ID.NO: 38AGCTACGAGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCCAGACCGCCAGAATCAGCTGCAGCGGCGACAGCATCCGGGAGTACTACGTGCACTGGTATCAGCAGAAGCCCGGCCAGGCTCCTGTGCTGGTGATCGGCGACGACACCAACAGACCCAGCGGCATCCCCGAGAGATTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCGAGGACGAGGCCGATTACTACTGCGCCGCCTGGGACTTCAGCCCTGCCATCGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCC CCTACAGAATGTTCA NVS966CDRH1 43/299 NYWIG (Kabat)/GYSFTNY (Chothia) CDRH2 44/300RIDPGESLTNYAPSFQG (Kabat)/DPGESL (Chothia) CDRH3 45/301TGVADVDMPFAH (Kabat)/TGVADVDMPFAH (Chothia) CDRL1 46/302SGDNLGSYYVN (Kabat)/DNLGSYY (Chothia) CDRL2 47/303GDSERPS (Kabat)/GDS (Chothia) CDRL3 48/304GSWDITSF (Kabat)/WDITSF (Chothia) VH 49EVQLVQSGAEVKKPGESLKISCKGSGYSFTNYWIGWVRQMPGKGLEWMGRIDPGESLTNYAPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARTGVADVDMPFAHWGQGTLVTVSS VL 50SYVLTQPPSVSVAPGKTARISCSGDNLGSYYVNWYQQKPGQAPVLVIYGDSERPSGIPERFSGSNSGNTATLTISRAQAGDEADYYCGSWDITSFV FGGGTKLTVL HEAVY CHAIN51 EVQLVQSGAEVKKPGESLKISCKGSGYSFTNYWIGWVRQMPGKGLEWMGRIDPGESLTNYAPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARTGVADVDMPFAHWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC LIGHT CHAIN 52SYVLTQPPSVSVAPGKTARISCSGDNLGSYYVNWYQQKPGQAPVLVIYGDSERPSGIPERFSGSNSGNTATLTISRAQAGDEADYYCGSWDITSFVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYS CQVTHEGSTVEKTVAPTECSPN ENCODING 53 SEQ.ID.NO: 49GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAGCCTGGCGAGAGCCTGAAGATCAGCTGCAAGGGCAGCGGCTACAGCTTCACCAACTACTGGATCGGCTGGGTGCGCCAGATGCCTGGCAAGGGCCTGGAATGGATGGGCAGAATCGACCCCGGCGAGTCCCTGACCAACTACGCCCCCAGCTTCCAGGGCCAGGTGACAATCAGCGCCGACAAGAGCATCAGCACCGCCTATCTGCAGTGGAGCAGCCTGAAGGCCAGCGACACCGCCATGTACTACTGCGCCAGAACCGGCGTGGCCGACGTGGACATGCCTTTTGCCCACTGGGGCCAGGGCACCCTGGTGACCGTGAGCTCA PN ENCODING 54 SEQ.ID.NO: 50AGCTACGTGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCAAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCTACTACGTGAACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACGGCGACAGCGAGAGGCCTAGCGGCATCCCCGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCTCTAGAGCCCAGGCCGGCGACGAGGCCGATTACTACTGCGGCTCCTGGGACATCACCAGCTTCGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTA PN ENCODING 55 SEQ.ID.NO: 51GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAGCCTGGCGAGAGCCTGAAGATCAGCTGCAAGGGCAGCGGCTACAGCTTCACCAACTACTGGATCGGCTGGGTGCGCCAGATGCCTGGCAAGGGCCTGGAATGGATGGGCAGAATCGACCCCGGCGAGTCCCTGACCAACTACGCCCCCAGCTTCCAGGGCCAGGTGACAATCAGCGCCGACAAGAGCATCAGCACCGCCTATCTGCAGTGGAGCAGCCTGAAGGCCAGCGACACCGCCATGTACTACTGCGCCAGAACCGGCGTGGCCGACGTGGACATGCCTTTTGCCCACTGGGGCCAGGGCACCCTGGTGACCGTGAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT PN ENCODING 56SEQ.ID.NO: 52 AGCTACGTGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCAAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCTACTACGTGAACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACGGCGACAGCGAGAGGCCTAGCGGCATCCCCGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCTCTAGAGCCCAGGCCGGCGACGAGGCCGATTACTACTGCGGCTCCTGGGACATCACCAGCTTCGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCT ACAGAATGTTCA NVS965CDRH1 57/305 SYAIS (Kabat)/GGTFNSY (Chothia) CDRH2 58/306RIIPIFGTANYAQKFQG (Kabat)/IPIFGT (Chothia) CDRH3 59/307HGGYSFDS (Kabat)/HGGYSFDS (Chothia) CDRL1 60/308SGDNLGSKYVD (Kabat)/DNLGSKY (Chothia) CDRL2 61/309SDNNRPS (Kabat)/SDN (Chothia) CDRL3 62/310ATYDSSPRTE (Kabat)/YDSSPRTE (Chothia) VH 63EVQLVQSGAEVKKPGSSVKVSCKASGGTFNSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYC ARHGGYSFDSWGQGTLVTVSSVL 64 SYVLTQPPSVSVAPGKTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCATYDSSPRT EVFGGGTKLTVLHEAVY CHAIN 65 EVQLVQSGAEVKKPGSSVKVSCKASGGTFNSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARHGGYSFDSWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC LIGHT CHAIN 66SYVLTQPPSVSVAPGKTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCATYDSSPRTEVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRS YSCQVTHEGSTVEKTVAPTECSPN ENCODING 67 SEQ.ID.NO: 63GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCAACAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACAGCTTCGATAGCTGGGGCCAGGGCACCCTG GTGACCGTGAGCTCAPN ENCODING 68 SEQ.ID.NO: 64AGCTACGTGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCAAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCATGGACGAGGCCGACTACTACTGCGCCACCTACGACAGCAGCCCCAGAACCGAGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTA PN ENCODING 69 SEQ.ID.NO: 65GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCAACAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACAGCTTCGATAGCTGGGGCCAGGGCACCCTGGTGACCGTGAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT PN ENCODING 70 SEQ.ID.NO: 66AGCTACGTGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCAAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCATGGACGAGGCCGACTACTACTGCGCCACCTACGACAGCAGCCCCAGAACCGAGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTG GCCCCTACAGAATGTTCANVS967 CDRH1 71/311 SHYMH (Kabat)/GYTFTSH (Chothia) CDRH2 72/312NINPVDGGTEYAQKFQG (Kabat)/NPVDGG (Chothia) CDRH3 73/313DGIEHGGHYYWGYLFDI (Kabat)/DGIEHGGHYYWGYLFDI (Chothia) CDRL1 74/314SGDSIREYYVH (Kabat)/DSIREYY (Chothia) CDRL2 75/315DDTNRPS (Kabat)/DDT (Chothia) CDRL3 76/316AAWDFSPAI (Kabat)/WDFSPAI (Chothia) VH 77EVQLVQSGAEVKKPGASVKVSCKASGYTFTSHYMHWVRQAPGQGLEWMGNINPVDGGTEYAQKFQGRVTMTRDTSISTAYMELSSLRSEDTAVYYCARDGIEHGGHYYWGYLFDIWGQGTLVTVSS VL 78SYVLTQPPSVSVAPGKTARISCSGDSIREYYVHWYQQKPGQAPVLVIGDDTNRPSGIPERFSGSNSGNTATLTISRAQAGDEADYYCAAWDFSPAI VFGGGTKLTVL HEAVY CHAIN79 EVQLVQSGAEVKKPGASVKVSCKASGYTFTSHYMHWVRQAPGQGLEWMGNINPVDGGTEYAQKFQGRVTMTRDTSISTAYMELSSLRSEDTAVYYCARDGIEHGGHYYWGYLFDIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC LIGHT CHAIN 80SYVLTQPPSVSVAPGKTARISCSGDSIREYYVHWYQQKPGQAPVLVIGDDTNRPSGIPERFSGSNSGNTATLTISRAQAGDEADYYCAAWDFSPAIVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSY SCQVTHEGSTVEKTVAPTECSPN ENCODING 81 SEQ.ID.NO: 77GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCTGGCGCCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCTACACCTTCACCAGCCACTACATGCACTGGGTGCGCCAGGCTCCAGGACAGGGCCTGGAATGGATGGGCAACATCAACCCCGTGGACGGCGGCACCGAGTACGCCCAGAAATTCCAGGGCAGAGTGACCATGACCCGGGACACCAGCATCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGCGCCAGGGACGGCATCGAGCACGGCGGCCACTACTACTGGGGCTACCTGTTCGACATCTGGGGCCAGGGCACCCTGGTGACCGTGAGCTCA PN ENCODING 82 SEQ.ID.NO: 78TCTTACGTGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCAAGACCGCCAGAATCAGCTGCAGCGGCGACAGCATCCGGGAGTACTACGTGCACTGGTATCAGCAGAAGCCCGGCCAGGCTCCTGTGCTGGTGATCGGCGACGACACCAACAGACCCAGCGGCATCCCCGAGAGATTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCTCTAGAGCCCAGGCCGGCGACGAGGCCGATTACTACTGCGCCGCCTGGGACTTCAGCCCTGCCATCGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTA PN ENCODING 83 SEQ.ID.NO: 79GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCTGGCGCCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCTACACCTTCACCAGCCACTACATGCACTGGGTGCGCCAGGCTCCAGGACAGGGCCTGGAATGGATGGGCAACATCAACCCCGTGGACGGCGGCACCGAGTACGCCCAGAAATTCCAGGGCAGAGTGACCATGACCCGGGACACCAGCATCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGCGCCAGGGACGGCATCGAGCACGGCGGCCACTACTACTGGGGCTACCTGTTCGACATCTGGGGCCAGGGCACCCTGGTGACCGTGAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTT GAGCCCAAATCTTGTPN ENCODING 84 SEQ.ID.NO: 80TCTTACGTGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCAAGACCGCCAGAATCAGCTGCAGCGGCGACAGCATCCGGGAGTACTACGTGCACTGGTATCAGCAGAAGCCCGGCCAGGCTCCTGTGCTGGTGATCGGCGACGACACCAACAGACCCAGCGGCATCCCCGAGAGATTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCTCTAGAGCCCAGGCCGGCGACGAGGCCGATTACTACTGCGCCGCCTGGGACTTCAGCCCTGCCATCGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCC CCTACAGAATGTTCA NVS807CDRH1 85/317 SYAIS (Kabat)/GGTFSSY (Chothia) CDRH2 86/318RIIPIFGTANYAQKFQG (Kabat)/IPIFGT (Chothia) CDRH3 87/319HGGYSYFDS (Kabat)/HGGYYFDS (Chothia) CDRL1 88/320SGDNLGSKYVD (Kabat)/DNLGSKY (Chothia) CDRL2 89/321SDNNRPS (Kabat)/SDN (Chothia) CDRL3 90/322QTYTSGNNYL (Kabat)/YTSGNNYL (Chothia) VH 91EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYC ARHGGYYFDSWGQGTLVTVSSVL 92 SYELTQPPSVSVAPGQTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTSGNNY LVFGGGTKLTVLHEAVY CHAIN 93 EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARHGGYYFDSWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC LIGHT CHAIN 94SYELTQPPSVSVAPGQTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTSGNNYLVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRS YSCQVTHEGSTVEKTVAPTECSPN ENCODING 95 SEQ.ID.NO: 91GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCAGCAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACTACTTCGATAGCTGGGGCCAGGGCACCCTG GTGACCGTGAGCTCAPN ENCODING 96 SEQ.ID.NO: 92AGCTACGAGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCCAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCGAGGACGAGGCCGACTACTACTGCCAGACCTACACCAGCGGCAACAACTACCTGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTA PN ENCODING 97 SEQ.ID.NO: 93GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCAGCAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACTACTTCGATAGCTGGGGCCAGGGCACCCTGGTGACCGTGAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT PN ENCODING 98 SEQ.ID.NO: 94AGCTACGAGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCCAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCGAGGACGAGGCCGACTACTACTGCCAGACCTACACCAGCGGCAACAACTACCTGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTG GCCCCTACAGAATGTTCANVS808 CDRH1 99/323 SYAIS (Kabat)/GGTFSSY (Chothia) CDRH2 100/324RIIPIFGTANYAQKFQG (Kabat)/IPIFGT (Chothia) CDRH3 101/325HGGYIFDS (Kabat)/HGGYIFDS (Chothia) CDRL1 102/326SGDNLGSKYVD (Kabat)/DNLGSKY (Chothia) CDRL2 103/327SDNNRPS (Kabat)/SDN (Chothia) CDRL3 104/328QTYTSGNNYL (Kabat)/YTSGNNYL (Chothia) VH 105EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYC ARHGGYIFDSWGQGTLVTVSSVL 106 SYELTQPPSVSVAPGQTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTSGNNY LVFGGGTKLTVLHEAVY CHAIN 107 EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARHGGYIFDSWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC LIGHT CHAIN 108SYELTQPPSVSVAPGQTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTSGNNYLVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRS YSCQVTHEGSTVEKTVAPTECSPN ENCODING 109 SEQ.ID.NO: 105GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCAGCAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACATTTTCGATAGCTGGGGCCAGGGCACCCTG GTGACCGTGAGCTCAPN ENCODING 110 SEQ.ID.NO: 106AGCTACGAGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCCAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCGAGGACGAGGCCGACTACTACTGCCAGACCTACACCAGCGGCAACAACTACCTGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTA PN ENCODING 111 SEQ.ID.NO: 107GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCAGCAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACATTTTCGATAGCTGGGGCCAGGGCACCCTGGTGACCGTGAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT PN ENCODING 112 SEQ.ID.NO: 108AGCTACGAGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCCAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCGAGGACGAGGCCGACTACTACTGCCAGACCTACACCAGCGGCAACAACTACCTGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTG GCCCCTACAGAATGTTCANVS806 CDRH1 113/329 SYAIS (Kabat)/GGTFSSY (Chothia) CDRH2 114/330RIIPIFGTANYAQKFQG (Kabat)/IPIFGT (Chothia) CDRH3 115/331HGGYVFDS (Kabat)/HGGYVFDS (Chothia) CDRL1 116/332SGDNLGSKYVD (Kabat)/DNLGSKY (Chothia) CDRL2 117/333SDNNRPS (Kabat)/SDN (Chothia) CDRL3 118/334QTYTSGNNYL (Kabat)/YTSGNNYL (Chothia) VH 119EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYC ARHGGYVFDSWGQGTLVTVSSVL 120 SYELTQPPSVSVAPGQTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTSGNNY LVFGGGTKLTVLHEAVY CHAIN 121 EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARHGGYVFDSWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC LIGHT CHAIN 122SYELTQPPSVSVAPGQTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTSGNNYLVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRS YSCQVTHEGSTVEKTVAPTECSPN ENCODING 123 SEQ.ID.NO: 119GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCAGCAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACGTCTTCGATAGCTGGGGCCAGGGCACCCTG GTGACCGTGAGCTCAPN ENCODING 124 SEQ.ID.NO: 120AGCTACGAGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCCAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCGAGGACGAGGCCGACTACTACTGCCAGACCTACACCAGCGGCAACAACTACCTGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTA PN ENCODING 125 SEQ.ID.NO: 121GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCAGCAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACGTCTTCGATAGCTGGGGCCAGGGCACCCTGGTGACCGTGAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT PN ENCODING 126 SEQ.ID.NO: 122AGCTACGAGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCCAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCGAGGACGAGGCCGACTACTACTGCCAGACCTACACCAGCGGCAACAACTACCTGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTG GCCCCTACAGAATGTTCANVS804 CDRH1 127/335 SYAIS (Kabat)/GGTFSSY (Chothia) CDRH2 128/336RIIPIFGTANYAQKFQG (Kabat)/IPIFGT (Chothia) CDRH3 129/337HGGYVFDS (Kabat)/HGGYIFDS (Chothia) CDRL1 130/338SGDNLGSKYVD (Kabat)/DNLGSKY (Chothia) CDRL2 131/339SDNNRPS (Kabat)/SDN (Chothia) CDRL3 132/340ATYDSSPRTE (Kabat)/YDSSPRTE (Chothia) VH 133EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYC ARHGGYIFDSWGQGTLVTVSSVL 134 SYVLTQPPSVSVAPGKTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCATYDSSPRT EVFGGGTKLTVLHEAVY CHAIN 135 EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARHGGYIFDSWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC LIGHT CHAIN 136SYVLTQPPSVSVAPGKTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCATYDSSPRTEVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRS YSCQVTHEGSTVEKTVAPTECSPN ENCODING 137 SEQ.ID.NO: 133GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCAGCAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACATTTTCGATAGCTGGGGCCAGGGCACCCTG GTGACCGTGAGCTCAPN ENCODING 138 SEQ.ID.NO: 134AGCTACGTGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCAAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCATGGACGAGGCCGACTACTACTGCGCCACCTACGACAGCAGCCCCAGAACCGAGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTA PN ENCODING 139 SEQ.ID.NO: 135GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCAGCAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACATTTTCGATAGCTGGGGCCAGGGCACCCTGGTGACCGTGAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT PN ENCODING 140 SEQ.ID.NO: 136AGCTACGTGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCAAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCATGGACGAGGCCGACTACTACTGCGCCACCTACGACAGCAGCCCCAGAACCGAGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTG GCCCCTACAGAATGTTCANVS809 CDRH1 141/341 SYAIS (Kabat)/GGTFSSY (Chothia) CDRH2 142/342RIIPIFGTANYAQKFQG (Kabat)/IPIFGT (Chothia) CDRH3 143/343HGGYYFDS (Kabat)/HGGYYFDS (Chothia) CDRL1 144/344SGDNLGSKYVD (Kabat)/DNLGSKY (Chothia) CDRL2 145/345SDNNRPS (Kabat)/SDN (Chothia) CDRL3 146/346ATYDSSPRTE (Kabat)/YDSSPRTE (Chothia) VH 147EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYC ARHGGYYFDSWGQGTLVTVSSVL 148 SYVLTQPPSVSVAPGKTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCATYDSSPRT EVFGGGTKLTVLHEAVY CHAIN 149 EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARHGGYYFDSWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC LIGHT CHAIN 150SYVLTQPPSVSVAPGKTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCATYDSSPRTEVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRS YSCQVTHEGSTVEKTVAPTECSPN ENCODING 151 SEQ.ID.NO: 147GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCAGCAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACTACTTCGATAGCTGGGGCCAGGGCACCCTG GTGACCGTGAGCTCAPN ENCODING 152 SEQ.ID.NO: 148AGCTACGTGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCAAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCATGGACGAGGCCGACTACTACTGCGCCACCTACGACAGCAGCCCCAGAACCGAGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTA PN ENCODING 153 SEQ.ID.NO: 149GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCAGCAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACTACTTCGATAGCTGGGGCCAGGGCACCCTGGTGACCGTGAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT PN ENCODING 154 SEQ.ID.NO: 150AGCTACGTGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCAAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCATGGACGAGGCCGACTACTACTGCGCCACCTACGACAGCAGCCCCAGAACCGAGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTG GCCCCTACAGAATGTTCANVS805 CDRH1 155/347 SYAIS (Kabat)/GGTFSSY (Chothia) CDRH2 156/348RIIPIFGTANYAQKFQG (Kabat)/IPIFGT (Chothia) CDRH3 157/349HGGYVFDS (Kabat)/HGGYVFDS (Chothia) CDRL1 158/350SGDNLGSKYVD (Kabat)/DNLGSKY (Chothia) CDRL2 159/351SDNNRPS (Kabat)/SDN (Chothia) CDRL3 160/352ATYDSSPRTE (Kabat)/YDSSPRTE (Chothia) VH 161EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYC ARHGGYVFDSWGQGTLVTVSSVL 162 SYVLTQPPSVSVAPGKTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCATYDSSPRT EVFGGGTKLTVLHEAVY CHAIN 163 EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARHGGYVFDSWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC LIGHT CHAIN 164SYVLTQPPSVSVAPGKTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCATYDSSPRTEVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRS YSCQVTHEGSTVEKTVAPTECSPN ENCODING 165 SEQ.ID.NO: 161GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCAGCAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACGTCTTCGATAGCTGGGGCCAGGGCACCCTG GTGACCGTGAGCTCAPN ENCODING 166 SEQ.ID.NO: 162AGCTACGTGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCAAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCATGGACGAGGCCGACTACTACTGCGCCACCTACGACAGCAGCCCCAGAACCGAGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTA PN ENCODING 167 SEQ.ID.NO: 163GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCAGCAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACGTCTTCGATAGCTGGGGCCAGGGCACCCTGGTGACCGTGAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT PN ENCODING 168 SEQ.ID.NO: 164AGCTACGTGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCAAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCATGGACGAGGCCGACTACTACTGCGCCACCTACGACAGCAGCCCCAGAACCGAGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTG GCCCCTACAGAATGTTCANVS962-S CDRH1 169/353 SYAIS (Kabat)/GGTFSSY (Chothia) CDRH2 170/354RIIPIFGTANYAQKFQG (Kabat)/IPIFGT (Chothia) CDRH3 171/355HGGYSFDS (Kabat)/HGGYSFDS (Chothia) CDRL1 172/356SGDNLGSKYVD (Kabat)/DNLGSKY (Chothia) CDRL2 173/357SDNNRPS (Kabat)/SDN (Chothia) CDRL3 174/358QTYTSGNNYL (Kabat)/YTSGNNYL (Chothia) VH 175EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYC ARHGGYSFDSWGQGTLVTVSSVL 176 SYELTQPPSVSVAPGQTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTSGNNY LVFGGGTKLTVLHEAVY CHAIN 177 EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARHGGYSFDSWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC LIGHT CHAIN 178SYELTQPPSVSVAPGQTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTSGNNYLVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRS YSCQVTHEGSTVEKTVAPTECSPN ENCODING 179 SEQ.ID.NO: 175GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCAGCAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACAGCTTCGATAGCTGGGGCCAGGGCACCCTG GTGACCGTGAGCTCAPN ENCODING 180 SEQ.ID.NO: 176AGCTACGAGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCCAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCGAGGACGAGGCCGACTACTACTGCCAGACCTACACCAGCGGCAACAACTACCTGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTA PN ENCODING 181 SEQ.ID.NO: 177GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCAGCAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACAGCTTCGATAGCTGGGGCCAGGGCACCCTGGTGACCGTGAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT PN ENCODING 182 SEQ.ID.NO: 178AGCTACGAGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCCAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCGAGGACGAGGCCGACTACTACTGCCAGACCTACACCAGCGGCAACAACTACCTGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTG GCCCCTACAGAATGTTCANVS962-Q CDRH1 183/359 SYAIS (Kabat)/GGTFQSY (Chothia) CDRH2 184/360RIIPIFGTANYAQKFQG (Kabat)/IPIFGT (Chothia) CDRH3 185/361HGGYSFDS (Kabat)/HGGYSFDS (Chothia) CDRL1 186/362SGDNLGSKYVD (Kabat)/DNLGSKY (Chothia) CDRL2 187/363SDNNRPS (Kabat)/SDN (Chothia) CDRL3 188/364QTYTSGNNYL (Kabat)/YTSGNNYL (Chothia) VH 189EVQLVQSGAEVKKPGSSVKVSCKASGGTFQSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYC ARHGGYSFDSWGQGTLVTVSSVL 190 SYELTQPPSVSVAPGQTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTSGNNY LVFGGGTKLTVLHEAVY CHAIN 191 EVQLVQSGAEVKKPGSSVKVSCKASGGTFQSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARHGGYSFDSWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC LIGHT CHAIN 192SYELTQPPSVSVAPGQTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTSGNNYLVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRS YSCQVTHEGSTVEKTVAPTECSPN ENCODING 193 SEQ.ID.NO: 189GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCCAAAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACAGCTTCGATAGCTGGGGCCAGGGCACCCTG GTGACCGTGAGCTCAPN ENCODING 194 SEQ.ID.NO: 190AGCTACGAGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCCAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCGAGGACGAGGCCGACTACTACTGCCAGACCTACACCAGCGGCAACAACTACCTGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTA PN ENCODING 195 SEQ.ID.NO: 191GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCCAAAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACAGCTTCGATAGCTGGGGCCAGGGCACCCTGGTGACCGTGAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT PN ENCODING 196 SEQ.ID.NO: 192AGCTACGAGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCCAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCGAGGACGAGGCCGACTACTACTGCCAGACCTACACCAGCGGCAACAACTACCTGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTG GCCCCTACAGAATGTTCANVS962-S31A CDRH1 197/365 SYAIS (Kabat)/GGTFNAY (Chothia) CDRH2 198/366RIIPIFGTANYAQKFQG (Kabat)/IPIFGT (Chothia) CDRH3 199/367HGGYSFDS (Kabat)/HGGYSFDS (Chothia) CDRL1 200/368SGDNLGSKYVD (Kabat)/DNLGSKY (Chothia) CDRL2 201/369SDNNRPS (Kabat)/SDN (Chothia) CDRL3 202/370QTYTSGNNYL (Kabat)/YTSGNNYL (Chothia) VH 203EVQLVQSGAEVKKPGSSVKVSCKASGGTFNAYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYC ARHGGYSFDSWGQGTLVTVSSVL 204 SYELTQPPSVSVAPGQTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTSGNNY LVFGGGTKLTVLHEAVY CHAIN 205 EVQLVQSGAEVKKPGSSVKVSCKASGGTFNAYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARHGGYSFDSWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC LIGHT CHAIN 206SYELTQPPSVSVAPGQTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTSGNNYLVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRS YSCQVTHEGSTVEKTVAPTECSPN ENCODING 207 SEQ.ID.NO: 203GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCAACGCCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACAGCTTCGATAGCTGGGGCCAGGGCACCCTG GTGACCGTGAGCTCAPN ENCODING 208 SEQ.ID.NO: 204AGCTACGAGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCCAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCGAGGACGAGGCCGACTACTACTGCCAGACCTACACCAGCGGCAACAACTACCTGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTA PN ENCODING 209 SEQ.ID.NO: 205GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCAACGCCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACAGCTTCGATAGCTGGGGCCAGGGCACCCTGGTGACCGTGAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT PN ENCODING 210 SEQ.ID.NO: 206AGCTACGAGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCCAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCGAGGACGAGGCCGACTACTACTGCCAGACCTACACCAGCGGCAACAACTACCTGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTG GCCCCTACAGAATGTTCANVS962-G CDRH1 211/371 SYAIS (Kabat)/GGTFGSY (Chothia) CDRH2 212/372RIIPIFGTANYAQKFQG (Kabat)/IPIFGT (Chothia) CDRH3 213/373HGGYSFDS (Kabat)/HGGYSFDS (Chothia) CDRL1 214/374SGDNLGSKYVD (Kabat)/DNLGSKY (Chothia) CDRL2 215/375SDNNRPS (Kabat)/SDN (Chothia) CDRL3 216/376QTYTSGNNYL (Kabat)/YTSGNNYL (Chothia) VH 217EVQLVQSGAEVKKPGSSVKVSCKASGGTFGSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYC ARHGGYSFDSWGQGTLVTVSSVL 218 SYELTQPPSVSVAPGQTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTSGNNY LVFGGGTKLTVLHEAVY CHAIN 219 EVQLVQSGAEVKKPGSSVKVSCKASGGTFGSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARHGGYSFDSWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC LIGHT CHAIN 220SYELTQPPSVSVAPGQTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTSGNNYLVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRS YSCQVTHEGSTVEKTVAPTECSPN ENCODING 221 SEQ.ID.NO: 217GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCGGCAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACAGCTTCGATAGCTGGGGCCAGGGCACCCTG GTGACCGTGAGCTCAPN ENCODING 222 SEQ.ID.NO: 218AGCTACGAGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCCAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCGAGGACGAGGCCGACTACTACTGCCAGACCTACACCAGCGGCAACAACTACCTGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTA PN ENCODING 223 SEQ.ID.NO: 219GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCGGCAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACAGCTTCGATAGCTGGGGCCAGGGCACCCTGGTGACCGTGAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT PN ENCODING 224 SEQ.ID.NO: 220AGCTACGAGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCCAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCGAGGACGAGGCCGACTACTACTGCCAGACCTACACCAGCGGCAACAACTACCTGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTG GCCCCTACAGAATGTTCANVS962-T CDRH1 225/377 SYAIS (Kabat)/GGTFTSY (Chothia) CDRH2 226/378RIIPIFGTANYAQKFQG (Kabat)/IPIFGT (Chothia) CDRH3 227/379HGGYSFDS (Kabat)/HGGYSFDS (Chothia) CDRL1 228/380SGDNLGSKYVD (Kabat)/DNLGSKY (Chothia) CDRL2 229/381SDNNRPS (Kabat)/SDN (Chothia) CDRL3 230/382QTYTSGNNYL (Kabat)/YTSGNNYL (Chothia) VH 231EVQLVQSGAEVKKPGSSVKVSCKASGGTFTSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYC ARHGGYSFDSWGQGTLVTVSSVL 232 SYELTQPPSVSVAPGQTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTSGNNY LVFGGGTKLTVLHEAVY CHAIN 233 EVQLVQSGAEVKKPGSSVKVSCKASGGTFTSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARHGGYSFDSWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC LIGHT CHAIN 234SYELTQPPSVSVAPGQTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTSGNNYLVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRS YSCQVTHEGSTVEKTVAPTECSPN ENCODING 235 SEQ.ID.NO: 231GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCACCAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACAGCTTCGATAGCTGGGGCCAGGGCACCCTG GTGACCGTGAGCTCAPN ENCODING 236 SEQ.ID.NO: 232AGCTACGAGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCCAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCGAGGACGAGGCCGACTACTACTGCCAGACCTACACCAGCGGCAACAACTACCTGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTA PN ENCODING 237 SEQ.ID.NO: 233GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCACCAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACAGCTTCGATAGCTGGGGCCAGGGCACCCTGGTGACCGTGAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT PN ENCODING 238 SEQ.ID.NO: 234AGCTACGAGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCCAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCGAGGACGAGGCCGACTACTACTGCCAGACCTACACCAGCGGCAACAACTACCTGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTG GCCCCTACAGAATGTTCANVS965-T CDRH1 239/383 SYAIS (Kabat)/GGTFTSY (Chothia) CDRH2 240/384RIIPIFGTANYAQKFQG (Kabat)/IPIFGT (Chothia) CDRH3 241/385HGGYSFDS (Kabat)/HGGYSFDS (Chothia) CDRL1 242/386SGDNLGSKYVD (Kabat)/DNLGSKY (Chothia) CDRL2 243/387SDNNRPS (Kabat)/SDN (Chothia) CDRL3 244/388ATYDSSPRTE (Kabat)/YDSSPRTE (Chothia) VH 245EVQLVQSGAEVKKPGSSVKVSCKASGGTFTSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYC ARHGGYSFDSWGQGTLVTVSSVL 246 SYVLTQPPSVSVAPGKTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCATYDSSPRT EVFGGGTKLTVLHEAVY CHAIN 247 EVQLVQSGAEVKKPGSSVKVSCKASGGTFTSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARHGGYSFDSWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC LIGHT CHAIN 248SYVLTQPPSVSVAPGKTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCATYDSSPRTEVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRS YSCQVTHEGSTVEKTVAPTECSPN ENCODING 249 SEQ.ID.NO: 245GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCACCAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACAGCTTCGATAGCTGGGGCCAGGGCACCCTG GTGACCGTGAGCTCAPN ENCODING 250 SEQ.ID.NO: 246AGCTACGTGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCAAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCATGGACGAGGCCGACTACTACTGCGCCACCTACGACAGCAGCCCCAGAACCGAGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTA PN ENCODING 251 SEQ.ID.NO: 247GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCACCAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACAGCTTCGATAGCTGGGGCCAGGGCACCCTGGTGACCGTGAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT PN ENCODING 252 SEQ.ID.NO: 248AGCTACGTGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCAAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCATGGACGAGGCCGACTACTACTGCGCCACCTACGACAGCAGCCCCAGAACCGAGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTG GCCCCTACAGAATGTTCANVS965-Q CDRH1 253/389 SYAIS (Kabat)/GGTFQSY (Chothia) CDRH2 254/390RIIPIFGTANYAQKFQG (Kabat)/IPIFGT (Chothia) CDRH3 255/391HGGYSFDS (Kabat)/HGGYSFDS (Chothia) CDRL1 256/392SGDNLGSKYVD (Kabat)/DNLGSKY (Chothia) CDRL2 257/393SDNNRPS (Kabat)/SDN (Chothia) CDRL3 258/394ATYDSSPRTE (Kabat)/YDSSPRTE (Chothia) VH 259EVQLVQSGAEVKKPGSSVKVSCKASGGTFQSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYC ARHGGYSFDSWGQGTLVTVSSVL 260 SYVLTQPPSVSVAPGKTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCATYDSSPRT EVFGGGTKLTVLHEAVY CHAIN 261 EVQLVQSGAEVKKPGSSVKVSCKASGGTFQSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARHGGYSFDSWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC LIGHT CHAIN 262SYVLTQPPSVSVAPGKTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCATYDSSPRTEVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRS YSCQVTHEGSTVEKTVAPTECSPN ENCODING 263 SEQ.ID.NO: 259GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCCAAAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACAGCTTCGATAGCTGGGGCCAGGGCACCCTG GTGACCGTGAGCTCAPN ENCODING 264 SEQ.ID.NO: 260AGCTACGTGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCAAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCATGGACGAGGCCGACTACTACTGCGCCACCTACGACAGCAGCCCCAGAACCGAGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTA PN ENCODING 265 SEQ.ID.NO: 261GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCCAAAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACAGCTTCGATAGCTGGGGCCAGGGCACCCTGGTGACCGTGAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT PN ENCODING 266 SEQ.ID.NO: 262AGCTACGTGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCAAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCATGGACGAGGCCGACTACTACTGCGCCACCTACGACAGCAGCCCCAGAACCGAGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTG GCCCCTACAGAATGTTCANVS965-S CDRH1 267/395 SYAIS (Kabat)/GGTFSSY (Chothia) CDRH2 268/396RIIPIFGTANYAQKFQG (Kabat)/IPIFGT (Chothia) CDRH3 269/397HGGYSFDS (Kabat)/HGGYSFDS (Chothia) CDRL1 270/398SGDNLGSKYVD (Kabat)/DNLGSKY (Chothia) CDRL2 271/399SDNNRPS (Kabat)/SDN (Chothia) CDRL3 272/400ATYDSSPRTE (Kabat)/YDSSPRTE (Chothia) VH 273EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYC ARHGGYSFDSWGQGTLVTVSSVL 274 SYVLTQPPSVSVAPGKTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCATYDSSPRT EVFGGGTKLTVLHEAVY CHAIN 275 EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARHGGYSFDSWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC LIGHT CHAIN 276SYVLTQPPSVSVAPGKTARISCSGDNLGSKYVDWYQQKPGQAPVLVIYSDNNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCATYDSSPRTEVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRS YSCQVTHEGSTVEKTVAPTECSPN ENCODING 277 SEQ.ID.NO: 273GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCAGCAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACAGCTTCGATAGCTGGGGCCAGGGCACCCTG GTGACCGTGAGCTCAPN ENCODING 278 SEQ.ID.NO: 274AGCTACGTGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCAAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCATGGACGAGGCCGACTACTACTGCGCCACCTACGACAGCAGCCCCAGAACCGAGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTA PN ENCODING 279 SEQ.ID.NO: 275GAGGTGCAGCTGGTGCAGAGCGGAGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCGGCACCTTCAGCAGCTACGCCATCAGCTGGGTGCGCCAGGCTCCTGGACAGGGCCTGGAATGGATGGGCCGGATCATCCCCATCTTCGGCACCGCCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGTGCCCGGCACGGCGGCTACAGCTTCGATAGCTGGGGCCAGGGCACCCTGGTGACCGTGAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT PN ENCODING 280 SEQ.ID.NO: 276AGCTACGTGCTGACTCAGCCCCCTTCTGTGTCTGTGGCCCCTGGCAAGACCGCCAGAATCAGCTGCAGCGGCGACAACCTGGGCAGCAAATACGTGGACTGGTATCAGCAGAAGCCCGGCCAGGCTCCCGTGCTGGTGATCTACAGCGACAACAACCGGCCCAGCGGCATCCCTGAGCGGTTCAGCGGCAGCAACAGCGGCAATACCGCCACCCTGACCATCAGCGGCACCCAGGCCATGGACGAGGCCGACTACTACTGCGCCACCTACGACAGCAGCCCCAGAACCGAGGTGTTCGGAGGCGGAACAAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTG GCCCCTACAGAATGTTCAHuman Factor P 401 NP_001138724.1PVLCFTQYEESSGKCKGLLGGGVSVEDCCLNTAFAYQKRSGGLCQPCRSPRWSLWSTWAPCSVTCSEGSQLRYRRCVGWNGQCSGKVAPGTLEWQLQACEDQQCCPEMGGWSGWGPWEPCSVTCSKGTRTRRRACNHPAPKCGGHCPGQAQESEACDTQQVCPTHGAWATWGPWTPCSASCHGGPHEPKETRSRKCSAPEPSQKPPGKPCPGLAYEQRRCTGLPPCPVAGGWGPWGPVSPCPVTCGLGQTMEQRTCNHPVPQHGGPFCAGDATRTHICNTAVPCPVDGEWDSWGEWSPCIRRNMKSISCQEIPGQQSRGRTCRGRKFDGHRCAGQQQDIRHCYSIQHCPLKGSWSEWSTWGLCMPPCGPNPTRARQRLCTPLLPKYPPTVSMVEGQGEKNVTFWGRPLPRCEELQGQKLVVEEKRPCLHVPA CKDPEEEEL Chimpanzee402 Factor P MITEGAQAPCLLLPPLLLLLTLPATGSDPVLCFTQYEESSGKCKGLLGXP_001136665.1 GGVSVKDCCLNTAYAYQERNGGLCQPCRSPRWSLWSTWAPCSVTCSEGSQLRYRRCVGWNGQCSERVALGTLEWQLQACEDKQCCPEMGGWSDWGPWEPCSVTCSKGMRTRRRACNHPAPKCGGHCPGEAQESEACDTQQVCPTHGAWAAWGPWSPCSGSCHGGPHEPKETRSRTCSAPEPSQKPPGKPCPGPAYEHRKCTGLPPCPVAGGWGPWGPVSPCPVTCGLGQTIERRTCNRPVPQHGGPSCAGDATRTHICNTAAPCPVDGEWDLWGQWSTCVRRNMKSISCEEIPGQQSRWRTCKGRKFDGHRCTGQQQDIRHCYSIQHCPLKGSWSEWSTWGLCMPPCGPNPTRARQRLCTPLLPKYPPTVSMVEGQGEKNVTFWGRPLPRCEELQGQKLVVEEKRPCLHVPACKDPEEEKL Rat Factor P 403 NP_001100227.1MPVGMQAPQWLLLLLLILPTTGSDPVLCFTQYEEPSGRCKGLLGRDIRVEDCCLNTAYAFQEHDGGLCQSCRSPQWSAWSSWGPCSVTCSEGSQLRHRRCVGRGGQCSEKAAPGTLEWQLQACEDQLCCPEMGGWSEWGPWGPCSVTCSKGTQTRQRLCDNPAPKCGGHCPGEAQQSQACDTQKICPTHGAWASWGPWSACSGSCLGGAQEPKETRSRSCSAPAPSHQPPGKPCSGTAYEHRGCSGLPPCPVAGGWGPWGPSSPCPVTCGLGQTLERRTCDHPVPRHGGPFCAGDATRKHVCNTAMPCPVNGEWEAWGKWSHCSRVRMKSISCDEIPGQQSRSRSCGGRKFDGQPCTGKLQDIRHCYDIHNCVLKGSWSQWSTWGLCTPPCGPNPTRVRQRLCTPLLPKYSPTVSMVEGQGEKNVTFWGIPRPLCEVLQGQKLVVEEKRPCLHVPSCRDPEEKKP Rabbit Factor P 404 XP_002719931.1MPAQAQPPLPLLLLPLLLTLPATGADPVVCFTEYDEPSGKCKGLLGGGVSVEHCCLNAAYAFQEPGSGLCHACRSPLWSPWSAWAPCSVTCSEGSQLRHRRCVGQGGPCSEKAAPGTLQWQLQACEDQPCCPEIGGWSDWGPWRPCSVTCSKGTKTRQRACDRPAPKCGGRCPGEAQESEACDTKQVCPTHGLWAAWGPWSPCSGSCHGGPQVPKETRSRTCSAPEPSKQPPGKPCSGPAYEEQSCAGLPPCPVAGGWGPWGPVSSCSVTCGLGKTLEKRTCDHPVPQHGGPFCTGDATRTHICNTAVPCPVNGEWEAWGEWSECSRPGRKSISCEEVPGQQRRTRVCKGRKFDGQRCAGEYQDIRHCYNIQRCRLKGSWLEWSSWGLCTPPCGPSPTRTRQRLCTALLPKFPPTISLVEGQGEKNVTFWGKPWPQCEQLQGQKLVVEEKRPCLHVPACKDPEEKP Mouse Factor P 405 NP_032849.2MPAEMQAPQWLLLLLVILPATGSDPVLCFTQYEESSGRCKGLLGRDIRVEDCCLNAAYAFQEHDGGLCQACRSPQWSAWSLWGPCSVTCSEGSQLRHRRCVGRGGQCSENVAPGTLEWQLQACEDQPCCPEMGGWSEWGPWGPCSVTCSKGTQIRQRVCDNPAPKCGGHCPGEAQQSQACDTQKTCPTHGAWASWGPWSPCSGSCLGGAQEPKETRSRSCSAPAPSHQPPGKPCSGPAYEHKACSGLPPCPVAGGWGPWSPLSPCSVTCGLGQTLEQRTCDHPAPRHGGPFCAGDATRNQMCNKAVPCPVNGEWEAWGKWSDCSRLRMSINCEGTPGQQSRSRSCGGRKFNGKPCAGKLQDIRHCYNIHNCIMKGSWSQWSTWSLCTPPCSPNATRVRQRLCTPLLPKYPPTVSMVEGQGEKNVTFWGTPRPLCEALQGQKLVVEEKRSCLHVPVCKDPEEKKP TSR5 Domain of 406 SEQ ID NO: 401VDGEWDSWGEWSPCIRRNMKSISCQEIPGQQSRGRTCRGRKFDGHRCA GQQQDIRHCYSIQHCPRegion B of TSR 407 5 domain PCIRRNMKSISCQEIPGQQSRGR Region of TSR 5 408binding domain KSISC TSR5 Domain of 409 mouse SEQ IDVNGEWEAWGKWSDCSRLRMSINCEGTPGQQSRSRSCGGRKFNGKPCAG NO: 405 KLQDIRHCYNIHNCI

TABLE 2 Examples of C5 Antibodies,  Fabs and C5 Proteins Antibody 8109Sequence Identifier (SEQ ID NO:) CDRH1 410 SYAIS CDRH2 411GIGPFFGTANYAQKFQG CDRH3 412 DTPYFDY CDRL1 413 SGDSIPNYYVY CDRL2 414DDSNRPS CDRL3 415 QSFDSSLNAEV VH 416EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIGPFFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDTPYFDYWGQGTLVTVSS VL 417SYELTQPLSVSVALGQTARITCSGDSIPNYYVYWYQQKPGQAPVLVIYDDSNRPSGIPERFSGSNSGNTATLTISRAQAGDEADYYCQSFDSSLNAEVFGGGTKLTVL Heavy chain 418EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIGPFFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDTPYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGKLight chain 419SYELTQPLSVSVALGQTARITCSGDSIPNYYVYWYQQKPGQAPVLVIYDDSNRPSGIPERFSGSNSGNTATLTISRAQAGDEADYYCQSFDSSLNAEVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS PN encoding 420 SEQ IDGAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAGC NO: 416TGCAAAGCCTCCGGAGGCACTTTTTCTTCTTATGCCATTTCTTGGGTGCGCCAAGCCCCTGGGCAGGGTCTCGAGTGGATGGGCGGTATCGGTCCGTTTTTTGGCACTGCGAATTACGCGCAGAAGTTTCAGGGCCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAGCCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGATACTCCTTATTTTGATTATTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA PN encoding 421 SEQ IDTCCTATGAACTCACACAGCCCCTGAGCGTGAGCGTGGCCCTGGGCCAGACCGCCCGGATCACC NO: 417TGCTCCGGCGACAGCATCCCCAACTACTACGTGTACTGGTACCAGCAGAAGCCCGGCCAGGCCCCCGTGCTGGTGATCTACGACGACAGCAACCGGCCCAGCGGCATCCCCGAGCGGTTCAGCGGCAGCAACAGCGGCAACACCGCCACCCTGACCATTTCCAGAGCACAGGCAGGCGACGAGGCCGACTACTACTGCCAGAGCTTCGACAGCAGCCTGAACGCCGAGGTGTTCGGCGGAGGGACCAAGTTAACCGTCCTA PN encoding 422 SEQ IDGAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAGC NO: 418TGCAAAGCCTCCGGAGGCACTTTTTCTTCTTATGCCATTTCTTGGGTGCGCCAAGCCCCTGGGCAGGGTCTCGAGTGGATGGGCGGTATCGGTCCGTTTTTTGGCACTGCGAATTACGCGCAGAAGTTTCAGGGCCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAGCCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGATACTCCTTATTTTGATTATTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCAGCGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA PN encoding 423 SEQ IDTCCTATGAACTCACACAGCCCCTGAGCGTGAGCGTGGCCCTGGGCCAGACCGCCCGGATCACC NO: 419TGCTCCGGCGACAGCATCCCCAACTACTACGTGTACTGGTACCAGCAGAAGCCCGGCCAGGCCCCCGTGCTGGTGATCTACGACGACAGCAACCGGCCCAGCGGCATCCCCGAGCGGTTCAGCGGCAGCAACAGCGGCAACACCGCCACCCTGACCATTTCCAGAGCACAGGCAGGCGACGAGGCCGACTACTACTGCCAGAGCTTCGACAGCAGCCTGAACGCCGAGGTGTTCGGCGGAGGGACCAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA Optimized PN 424 encoding SEQGAGGTGCAGCTGGTGCAGAGCGGAGCCGAGGTGAAGAAGCCCGGTAGCAGCGTCAAGGTGTCCID NO: 418TGCAAGGCCAGCGGCGGCACCTTCAGCAGCTACGCCATCAGCTGGGTGCGGCAGGCCCCAGGCCAGGGCCTGGAGTGGATGGGCGGCATCGGCCCATTCTTCGGCACCGCCAACTACGCCCAGAAGTTCCAGGGCAGGGTCACCATCACCGCCGACGAGAGCACCAGCACCGCCTACATGGAGCTGTCCAGCCTGAGAAGCGAGGACACCGCCGTGTACTACTGCGCCAGAGACACCCCCTACTTCGACTACTGGGGCCAGGGCACCCTGGTGACCGTGAGCAGCGCTAGCACCAAGGGCCCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCTCCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGTCCAGCGTGGTGACAGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAGCCCCCGAAGCTGCAGGCGGCCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGAGCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAGTGCAAGGTCTCCAACAAGGCCCTGCCTGCCCCCATCGAAAAGACCATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCTTCTCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCACCCGGCAAG Optimized PN 425 encoding SEQAGCTACGAGCTGACCCAGCCCCTGAGCGTGAGCGTGGCCCTGGGCCAGACCGCCAGGATCACCID NO: 419TGCAGCGGCGACAGCATCCCCAACTACTACGTGTACTGGTATCAGCAGAAGCCCGGCCAGGCCCCCGTGCTGGTGATCTACGACGACAGCAACAGGCCCAGCGGCATCCCCGAGAGGTTCAGCGGCAGCAACAGCGGCAACACCGCCACCCTGACCATCAGCAGAGCCCAGGCCGGCGACGAGGCCGACTACTACTGCCAGAGCTTCGACAGCTCACTGAACGCCGAGGTGTTCGGCGGAGGGACCAAGCTGACCGTGCTGGGCCAGCCTAAGGCTGCCCCCAGCGTGACCCTGTTCCCCCCCAGCAGCGAGGAGCTGCAGGCCAACAAGGCCACCCTGGTGTGCCTGATCAGCGACTTCTACCCAGGCGCCGTGACCGTGGCCTGGAAGGCCGACAGCAGCCCCGTGAAGGCCGGCGTGGAGACCACCACCCCCAGCAAGCAGAGCAACAACAAGTACGCCGCCAGCAGCTACCTGAGCCTGACCCCCGAGCAGTGGAAGAGCCACAGGTCCTACAGCTGCCAGGTGACCCACGAGGGCAGCACCGTGGAAAAGACCGTGGCCCCAACCGAGTGCAGC Antibody 8110Sequence Identifier (SEQ ID NO:) and Sequence or comments CDRH1 426 NYISCDRH2 427 IIDPDDSYTEYSPSFQG CDRH3 428 YEYGGFDI CDRL1 429 SGDNIGNSYVHCDRL2 430 KDNDRPS CDRL3 431 GTYDIESYV VH 432EVQLVQSGAEVKKPGESLKISCKGSGYSFTNYISWVRQMPGKGLEWMGIIDPDDSYTEYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARYEYGGFDIWGQGTLVTVSS VL 433SYELTQPPSVSVAPGQTARISCSGDNIGNSYVHWYQQKPGQAPVLVIYKDNDRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCGTYDIESYVFGGGTKLTVL Heavy chain 434EVQLVQSGAEVKKPGESLKISCKGSGYSFTNYISWVRQMPGKGLEWMGIIDPDDSYTEYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARYEYGGFDIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGKLight chain 435SYELTQPPSVSVAPGQTARISCSGDNIGNSYVHWYQQKPGQAPVLVIYKDNDRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCGTYDIESYVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS PN encoding 436 SEQ IDGAGGTGCAATTGGTTCAGAGCGGCGCGGAAGTGAAAAAACCGGGCGAAAGCCTGAAAATTAGC NO: 432TGCAAAGGTTCCGGATATTCCTTTACTAATTATATTTCTTGGGTGCGCCAGATGCCTGGGAAGGGTCTCGAGTGGATGGGCATTATTGATCCTGATGATTCTTATACTGAGTATTCTCCTTCTTTTCAGGGTCAGGTCACCATTAGCGCGGATAAAAGCATTAGCACCGCGTATCTTCAATGGAGCAGCCTGAAAGCGAGCGATACGGCCATGTATTATTGCGCGCGTTATGAGTATGGTGGTTTTGATATTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA PN encoding 437 SEQ IDAGTTACGAACTGACCCAGCCGCCTTCAGTGAGCGTTGCACCAGGTCAGACCGCGCGTATCTCG NO: 434TGTAGCGGCGATAATATTGGTAATTCTTATGTTCATTGGTACCAGCAGAAACCCGGGCAGGCGCCAGTTCTTGTGATTTATAAGGATAATGATCGTCCCTCAGGCATCCCGGAACGCTTTAGCGGATCCAACAGCGGCAACACCGCGACCCTGACCATTAGCGGCACTCAGGCGGAAGACGAAGCGGATTATTATTGCGGTACTTATGATATTGAGTCTTATGTGTTTGGCGGCGGCACGAAGTTAACCGTC CTAPN encoding 438 SEQ IDGAGGTGCAATTGGTTCAGAGCGGCGCGGAAGTGAAAAAACCGGGCGAAAGCCTGAAAATTAGC NO: 435TGCAAAGGTTCCGGATATTCCTTTACTAATTATATTTCTTGGGTGCGCCAGATGCCTGGGAAGGGTCTCGAGTGGATGGGCATTATTGATCCTGATGATTCTTATACTGAGTATTCTCCTTCTTTTCAGGGTCAGGTCACCATTAGCGCGGATAAAAGCATTAGCACCGCGTATCTTCAATGGAGCAGCCTGAAAGCGAGCGATACGGCCATGTATTATTGCGCGCGTTATGAGTATGGTGGTTTTGATATTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCAGCGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA PN encoding 439 SEQ IDAGTTACGAACTGACCCAGCCGCCTTCAGTGAGCGTTGCACCAGGTCAGACCGCGCGTATCTCG NO: 436TGTAGCGGCGATAATATTGGTAATTCTTATGTTCATTGGTACCAGCAGAAACCCGGGCAGGCGCCAGTTCTTGTGATTTATAAGGATAATGATCGTCCCTCAGGCATCCCGGAACGCTTTAGCGGATCCAACAGCGGCAACACCGCGACCCTGACCATTAGCGGCACTCAGGCGGAAGACGAAGCGGATTATTATTGCGGTACTTATGATATTGAGTCTTATGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA TGTTCAOptimized PN 440 encoding SEQGAGGTGCAGCTGGTGCAGAGCGGAGCCGAGGTGAAAAAGCCCGGTGAGAGCCTGAAGATCAGCID NO: 434TGCAAGGGCAGCGGCTACAGCTTCACCAACTACATCAGCTGGGTGCGGCAGATGCCCGGCAAGGGCCTGGAGTGGATGGGCATCATCGACCCCGACGACAGCTACACCGAGTACAGCCCCAGCTTCCAGGGCCAGGTGACCATCAGCGCCGACAAGAGCATCAGCACCGCCTACCTGCAGTGGAGCAGCCTGAAGGCCAGCGACACCGCCATGTACTACTGCGCCAGATACGAGTACGGCGGCTTCGACATCTGGGGCCAGGGCACCCTGGTGACCGTCAGCTCAGCTAGCACCAAGGGCCCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCTCCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGTCCAGCGTGGTGACAGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAGCCCCCGAAGCTGCAGGCGGCCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGAGCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAGTGCAAGGTCTCCAACAAGGCCCTGCCTGCCCCCATCGAAAAGACCATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCTTCTCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCACCCGGCAAG Optimized PN 441 encoding SEQAGCTACGAGCTGACCCAGCCCCCCAGCGTGAGCGTGGCCCCAGGCCAGACCGCCAGGATCAGCID NO: 435TGCAGCGGCGACAACATCGGCAACAGCTACGTGCACTGGTATCAGCAGAAGCCCGGCCAGGCCCCCGTGCTGGTGATCTACAAGGACAACGACAGGCCCAGCGGCATCCCCGAGAGGTTCAGCGGCAGCAACTCCGGCAACACCGCCACCCTGACCATCAGCGGCACCCAGGCCGAGGACGAGGCCGACTACTACTGCGGCACCTACGACATCGAGTCATACGTGTTCGGCGGAGGGACCAAGCTGACCGTGCTGGGCCAGCCTAAGGCTGCCCCCAGCGTGACCCTGTTCCCCCCCAGCAGCGAGGAGCTGCAGGCCAACAAGGCCACCCTGGTGTGCCTGATCAGCGACTTCTACCCAGGCGCCGTGACCGTGGCCTGGAAGGCCGACAGCAGCCCCGTGAAGGCCGGCGTGGAGACCACCACCCCCAGCAAGCAGAGCAACAACAAGTACGCCGCCAGCAGCTACCTGAGCCTGACCCCCGAGCAGTGGAAGAGCCACAGGTCCTACAGCTGCCAGGTGACCCACGAGGGCAGCACCGTGGAAAAGACCGTGGCCCCAACCGAG TGCAGCAntibody 8111 Sequence Identifier (SEQ ID NO:) and Sequence or commentsCDRH1 442 TSGGGVS CDRH2 443 NIDDADIKDYSPSLKS CDRH3 444 GPYGFDS CDRL1 445TGTSSDIGTYNYVS CDRL2 446 DDSNRPS CDRL3 447 QSYDSQSIV VH 448EVTLKESGPALVKPTQTLTLTCTFSGFSLSTSGGGVSWIRQPPGKALEWLANIDDADIKDYSPSLKSRLTISKDTSKNQVVLTMTNMDPVDTATYYCARGPYGFDSWGQGTLVTVSS VL 449ESALTQPASVSGSPGQSITISCTGTSSDIGTYNYVSWYQQHPGKAPKLMIYDDSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCQSYDSQSIVFGGGTKLTVL Heavy chain 450EVTLKESGPALVKPTQTLTLTCTFSGFSLSTSGGGVSWIRQPPGKALEWLANIDDADIKDYSPSLKSRLTISKDTSKNQVVLTMTNMDPVDTATYYCARGPYGFDSWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGKLight chain 451ESALTQPASVSGSPGQSITISCTGTSSDIGTYNYVSWYQQHPGKAPKLMIYDDSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCQSYDSQSIVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS PN encoding 452 SEQ IDGAGGTGACATTGAAAGAAAGCGGCCCGGCCCTGGTGAAACCGACCCAAACCCTGACCCTGACC NO: 448TGTACCTTTTCCGGATTTAGCCTGTCTACTTCTGGTGGTGGTGTGTCTTGGATTCGCCAGCCGCCTGGGAAAGCCCTCGAGTGGCTGGCTAATATTGATGATGCTGATATTAAGGATTATTCTCCTTCTCTTAAGTCTCGTCTGACCATTAGCAAAGATACTTCGAAAAATCAGGTGGTGCTGACTATGACCAACATGGACCCGGTGGATACGGCCACCTATTATTGCGCGCGTGGTCCTTATGGTTTTGATTCTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA PN encoding 453 SEQ IDGAAAGCGCACTGACCCAGCCAGCTTCAGTGAGCGGCTCACCAGGTCAGAGCATTACCATCTCG NO: 449TGTACGGGTACTAGCAGCGATATTGGTACTTATAATTATGTGTCTTGGTACCAGCAGCATCCCGGGAAGGCGCCGAAACTTATGATTTATGATGATTCTAATCGTCCCTCAGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTATTGCCAGTCTTATGATTCTCAGTCTATTGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA PN encoding 454 SEQ IDGAGGTGACATTGAAAGAAAGCGGCCCGGCCCTGGTGAAACCGACCCAAACCCTGACCCTGACC NO: 450TGTACCTTTTCCGGATTTAGCCTGTCTACTTCTGGTGGTGGTGTGTCTTGGATTCGCCAGCCGCCTGGGAAAGCCCTCGAGTGGCTGGCTAATATTGATGATGCTGATATTAAGGATTATTCTCCTTCTCTTAAGTCTCGTCTGACCATTAGCAAAGATACTTCGAAAAATCAGGTGGTGCTGACTATGACCAACATGGACCCGGTGGATACGGCCACCTATTATTGCGCGCGTGGTCCTTATGGTTTTGATTCTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCAGCGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA PN encoding 455 SEQ IDGAAAGCGCACTGACCCAGCCAGCTTCAGTGAGCGGCTCACCAGGTCAGAGCATTACCATCTCG NO: 451TGTACGGGTACTAGCAGCGATATTGGTACTTATAATTATGTGTCTTGGTACCAGCAGCATCCCGGGAAGGCGCCGAAACTTATGATTTATGATGATTCTAATCGTCCCTCAGGCGTGAGCAACCGTTTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGACGAAGCGGATTATTATTGCCAGTCTTATGATTCTCAGTCTATTGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA Optimized PN 456 encoding SEQGAGGTGACCCTGAAGGAGAGCGGCCCAGCCCTGGTGAAGCCCACCCAGACCCTGACCCTGACTID NO: 448TGCACCTTCAGCGGCTTCAGCCTGAGCACCAGCGGAGGGGGCGTGAGCTGGATCAGGCAGCCCCCAGGTAAGGCCCTGGAGTGGCTGGCCAATATCGACGACGCCGATATCAAGGACTACAGCCCCAGCCTGAAGAGCAGGCTGACCATCAGCAAGGACACCAGCAAGAACCAGGTGGTGCTGACCATGACCAATATGGACCCCGTGGACACCGCCACCTACTACTGCGCCAGAGGCCCCTACGGCTTCGACAGCTGGGGCCAGGGCACCCTGGTGACCGTCAGCTCAGCTAGCACCAAGGGCCCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCTCCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGTCCAGCGTGGTGACAGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAGCCCCCGAAGCTGCAGGCGGCCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGAGCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAGTGCAAGGTCTCCAACAAGGCCCTGCCTGCCCCCATCGAAAAGACCATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCTTCTCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCACCCGGCAAG Optimized PN 457 encoding SEQGAGAGCGCCCTGACCCAGCCCGCCAGCGTGAGCGGCAGCCCAGGCCAGTCTATCACAATCAGCID NO: 449TGCACCGGCACCTCCAGCGATATCGGCACCTACAACTACGTGAGCTGGTATCAGCAGCACCCCGGCAAGGCCCCCAAGCTGATGATCTACGACGACAGCAACAGGCCCAGCGGCGTGAGCAACAGGTTCAGCGGCAGCAAGAGCGGCAACACCGCCAGCCTGACAATCAGCGGCCTGCAGGCCGAGGACGAGGCCGACTACTACTGCCAGAGCTACGACAGCCAGTCAATCGTGTTCGGCGGAGGGACCAAGCTGACCGTGCTGGGCCAGCCTAAGGCTGCCCCCAGCGTGACCCTGTTCCCCCCCAGCAGCGAGGAGCTGCAGGCCAACAAGGCCACCCTGGTGTGCCTGATCAGCGACTTCTACCCAGGCGCCGTGACCGTGGCCTGGAAGGCCGACAGCAGCCCCGTGAAGGCCGGCGTGGAGACCACCACCCCCAGCAAGCAGAGCAACAACAAGTACGCCGCCAGCAGCTACCTGAGCCTGACCCCCGAGCAGTGGAAGAGCCACAGGTCCTACAGCTGCCAGGTGACCCACGAGGGCAGCACCGTGGAAAAGACCGTGGCCCCAACCGAGTGCAGC Antibody 8113Sequence Identifier (SEQ ID NO:) and Sequence or comments CDRH1SEQ ID NO: 426 CDRH2 458 IIDPDDSYTRYSPSFQG CDRH3 SEQ ID NO: 428 CDRL1SEQ ID NO: 429 CDRL2 SEQ ID NO: 430 CDRL3 459 ATWGSEDQV VH 460EVQLVQSGAEVKKPGESLKISCKGSGYSFTNYISWVRQMPGKGLEWMGIIDPDDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARYEYGGFDIWGQGTLVTVSS VL 461SYELTQPPSVSVAPGQTARISCSGDNIGNSYVHWYQQKPGQAPVLVIYKDNDRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCATWGSEDQVFGGGTKLTVL Heavy chain 462EVQLVQSGAEVKKPGESLKISCKGSGYSFTNYISWVRQMPGKGLEWMGIIDPDDSYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARYEYGGFDIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGKLight chain 463SYELTQPPSVSVAPGQTARISCSGDNIGNSYVHWYQQKPGQAPVLVIYKDNDRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCATWGSEDQVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS PN encoding 464 SEQ IDGAGGTGCAATTGGTTCAGAGCGGCGCGGAAGTGAAAAAACCGGGCGAAAGCCTGAAAATTAGC NO: 460TGCAAAGGTTCCGGATATTCCTTTACTAATTATATTTCTTGGGTGCGCCAGATGCCTGGGAAGGGTCTCGAGTGGATGGGCATTATCGATCCGGATGATAGCTATACCCGTTATTCTCCGAGCTTTCAGGGACAGGTGACCATTAGCGCGGATAAAAGCATTAGCACCGCGTATCTTCAATGGAGCAGCCTGAAAGCGAGCGATACGGCCATGTATTATTGCGCGCGTTATGAGTATGGTGGTTTTGATATTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA PN encoding 465 SEQ IDAGTTACGAACTGACCCAGCCGCCTTCAGTGAGCGTTGCACCAGGTCAGACCGCGCGTATCTCG NO: 461TGTAGCGGCGATAATATTGGTAATTCTTATGTTCATTGGTACCAGCAGAAACCCGGGCAGGCGCCAGTTCTTGTGATTTATAAGGATAATGATCGTCCCTCAGGCATCCCGGAACGCTTTAGCGGATCCAACAGCGGCAACACCGCGACCCTGACCATTAGCGGCACTCAGGCGGAAGACGAAGCGGATTATTATTGCGCTACTTGGGGTTCTGAGGATCAGGTGTTTGGCGGCGGCACGAAGTTAACCGTC CTAPN encoding 466 SEQ IDGAGGTGCAATTGGTTCAGAGCGGCGCGGAAGTGAAAAAACCGGGCGAAAGCCTGAAAATTAGC NO: 462TGCAAAGGTTCCGGATATTCCTTTACTAATTATATTTCTTGGGTGCGCCAGATGCCTGGGAAGGGTCTCGAGTGGATGGGCATTATCGATCCGGATGATAGCTATACCCGTTATTCTCCGAGCTTTCAGGGACAGGTGACCATTAGCGCGGATAAAAGCATTAGCACCGCGTATCTTCAATGGAGCAGCCTGAAAGCGAGCGATACGGCCATGTATTATTGCGCGCGTTATGAGTATGGTGGTTTTGATATTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCAGCGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA PN encoding 467 SEQ IDAGTTACGAACTGACCCAGCCGCCTTCAGTGAGCGTTGCACCAGGTCAGACCGCGCGTATCTCG NO: 463TGTAGCGGCGATAATATTGGTAATTCTTATGTTCATTGGTACCAGCAGAAACCCGGGCAGGCGCCAGTTCTTGTGATTTATAAGGATAATGATCGTCCCTCAGGCATCCCGGAACGCTTTAGCGGATCCAACAGCGGCAACACCGCGACCCTGACCATTAGCGGCACTCAGGCGGAAGACGAAGCGGATTATTATTGCGCTACTTGGGGTTCTGAGGATCAGGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA TGTTCAOptimized PN 468 encoding SEQGAGGTGCAGCTGGTGCAGAGCGGAGCCGAGGTGAAAAAGCCCGGTGAGAGCCTGAAGATCAGCID NO: 462TGCAAGGGCAGCGGCTACAGCTTCACCAACTACATCAGCTGGGTGCGGCAGATGCCCGGCAAGGGCCTGGAGTGGATGGGCATCATCGACCCCGACGACAGCTACACCAGGTACAGCCCCAGCTTCCAGGGCCAGGTGACCATCAGCGCCGACAAGAGCATCAGCACCGCCTACCTGCAGTGGAGCAGCCTGAAGGCCAGCGACACCGCCATGTACTACTGCGCCAGATACGAGTACGGCGGCTTCGACATCTGGGGCCAGGGCACCCTGGTGACCGTCAGCTCAGCTAGCACCAAGGGCCCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCTCCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGTCCAGCGTGGTGACAGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAGCCCCCGAAGCTGCAGGCGGCCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGAGCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAGTGCAAGGTCTCCAACAAGGCCCTGCCTGCCCCCATCGAAAAGACCATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCTTCTCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCACCCGGCAAG Optimized PN 469 encoding SEQAGCTACGAGCTGACCCAGCCCCCCAGCGTGAGCGTGGCCCCAGGCCAGACCGCCAGGATCAGCID NO: 463TGCAGCGGCGACAATATCGGCAACAGCTACGTGCACTGGTATCAGCAGAAGCCCGGCCAGGCCCCCGTGCTGGTGATCTACAAGGACAACGACAGGCCCAGCGGCATCCCCGAGAGGTTCAGCGGCAGCAACTCCGGCAACACCGCCACCCTGACAATCAGCGGCACCCAGGCCGAGGACGAGGCCGACTACTACTGCGCCACCTGGGGCTCAGAGGACCAGGTGTTCGGCGGAGGGACCAAGCTGACCGTGCTGGGCCAGCCTAAGGCTGCCCCCAGCGTGACCCTGTTCCCCCCCAGCAGCGAGGAGCTGCAGGCCAACAAGGCCACCCTGGTGTGCCTGATCAGCGACTTCTACCCAGGCGCCGTGACCGTGGCCTGGAAGGCCGACAGCAGCCCCGTGAAGGCCGGCGTGGAGACCACCACCCCCAGCAAGCAGAGCAACAACAAGTACGCCGCCAGCAGCTACCTGAGCCTGACCCCCGAGCAGTGGAAGAGCCACAGGTCCTACAGCTGCCAGGTGACCCACGAGGGCAGCACCGTGGAAAAGACCGTGGCCCCAACCGAG TGCAGCAntibody 8114 Sequence Identifier (SEQ ID NO:) and Sequence or commentsCDRH1 470 SYYIG CDRH2 471 IIDPTDSQTAYSPSFQG CDRH3 472 YMMRGFDH CDRL1 473SGDSLGDYYAY CDRL2 474 KDNNRPS CDRL3 475 QTWDTGESGV VH 476EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYYIGWVRQMPGKGLEWMGIIDPTDSQTAYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARYMMRGFDHWGQGTLVTVSS VL 477SYELTQPPSVSVAPGQTARISCSGDSLGDYYAYWYQQKPGQAPVLVIYKDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTWDTGESGVFGGGTKLTVL Heavy chain 478EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYYIGWVRQMPGKGLEWMGIIDPTDSQTAYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARYMMRGFDHWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGKLight chain 479SYELTQPPSVSVAPGQTARISCSGDSLGDYYAYWYQQKPGQAPVLVIYKDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTWDTGESGVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS PN encoding 480 SEQ IDGAGGTGCAATTGGTTCAGAGCGGCGCGGAAGTGAAAAAACCGGGCGAAAGCCTGAAAATTAGC NO: 476TGCAAAGGTTCCGGATATTCCTTTACTTCTTATTATATTGGTTGGGTGCGCCAGATGCCTGGGAAGGGTCTCGAGTGGATGGGCATTATTGATCCTACTGATTCTCAGACTGCTTATTCTCCTTCTTTTCAGGGTCAGGTGACCATTAGCGCGGATAAAAGCATTAGCACCGCGTATCTTCAATGGAGCAGCCTGAAAGCGAGCGATACGGCCATGTATTATTGCGCGCGTTATATGATGCGTGGTTTTGATCATTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA PN encoding 481 SEQ IDAGTTACGAACTGACCCAGCCGCCTTCAGTGAGCGTTGCACCAGGTCAGACCGCGCGTATCTCG NO: 478TGTAGCGGCGATTCTCTTGGTGATTATTATGCTTATTGGTACCAGCAGAAACCCGGGCAGGCGCCAGTTCTTGTGATTTATAAGGATAATAATCGTCCCTCAGGCATCCCGGAACGCTTTAGCGGATCCAACAGCGGCAACACCGCGACCCTGACCATTAGCGGCACTCAGGCGGAAGACGAAGCGGATTATTATTGCCAGACTTGGGATACTGGTGAGTCTGGTGTGTTTGGCGGCGGCACGAAGTTAACC GTCCTAPN encoding 482 SEQ IDGAGGTGCAATTGGTTCAGAGCGGCGCGGAAGTGAAAAAACCGGGCGAAAGCCTGAAAATTAGC NO: 479TGCAAAGGTTCCGGATATTCCTTTACTTCTTATTATATTGGTTGGGTGCGCCAGATGCCTGGGAAGGGTCTCGAGTGGATGGGCATTATTGATCCTACTGATTCTCAGACTGCTTATTCTCCTTCTTTTCAGGGTCAGGTGACCATTAGCGCGGATAAAAGCATTAGCACCGCGTATCTTCAATGGAGCAGCCTGAAAGCGAGCGATACGGCCATGTATTATTGCGCGCGTTATATGATGCGTGGTTTTGATCATTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCAGCGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA PN encoding 483 SEQ IDAGTTACGAACTGACCCAGCCGCCTTCAGTGAGCGTTGCACCAGGTCAGACCGCGCGTATCTCG NO: 480TGTAGCGGCGATTCTCTTGGTGATTATTATGCTTATTGGTACCAGCAGAAACCCGGGCAGGCGCCAGTTCTTGTGATTTATAAGGATAATAATCGTCCCTCAGGCATCCCGGAACGCTTTAGCGGATCCAACAGCGGCAACACCGCGACCCTGACCATTAGCGGCACTCAGGCGGAAGACGAAGCGGATTATTATTGCCAGACTTGGGATACTGGTGAGTCTGGTGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA Optimized PN 484 encoding SEQGAGGTGCAGCTGGTGCAGAGCGGAGCCGAGGTGAAAAAGCCCGGTGAGAGCCTGAAGATCAGCID NO: 479TGCAAGGGCAGCGGCTACAGCTTCACCAGCTACTACATCGGCTGGGTGCGGCAGATGCCCGGCAAGGGCCTGGAGTGGATGGGCATCATCGACCCCACCGACAGCCAGACCGCCTACAGCCCCAGCTTCCAGGGCCAGGTGACCATCAGCGCCGACAAGAGCATCAGCACCGCCTACCTGCAGTGGAGCAGCCTGAAGGCCAGCGACACCGCCATGTACTACTGCGCCCGGTACATGATGAGGGGCTTCGACCACTGGGGTCAGGGCACCCTGGTGACCGTCAGCTCAGCTAGCACCAAGGGCCCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCTCCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGTCCAGCGTGGTGACAGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAGCCCCCGAAGCTGCAGGCGGCCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGAGCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAGTGCAAGGTCTCCAACAAGGCCCTGCCTGCCCCCATCGAAAAGACCATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCTTCTCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCACCCGGCAAG Optimized PN 485 encoding SEQAGCTACGAGCTGACCCAGCCCCCCAGCGTGAGCGTGGCCCCAGGCCAGACCGCCAGGATCAGCID NO: 480TGCAGCGGCGACAGCCTGGGCGACTACTACGCCTACTGGTATCAGCAGAAGCCCGGCCAGGCCCCCGTGCTGGTGATCTACAAGGACAACAACAGGCCCAGCGGCATCCCCGAGAGGTTCAGCGGCAGCAACAGCGGCAACACCGCCACCCTGACAATCAGCGGCACCCAGGCCGAGGACGAGGCCGACTACTACTGCCAGACCTGGGACACCGGCGAGTCAGGCGTGTTCGGCGGAGGGACCAAGCTGACCGTGCTGGGTCAGCCTAAGGCTGCCCCCAGCGTGACCCTGTTCCCCCCCAGCAGCGAGGAGCTGCAGGCCAACAAGGCCACCCTGGTGTGCCTGATCAGCGACTTCTACCCAGGCGCCGTGACCGTGGCCTGGAAGGCCGACAGCAGCCCCGTGAAGGCCGGCGTGGAGACCACCACCCCCAGCAAGCAGAGCAACAACAAGTACGCCGCCAGCAGCTACCTGAGCCTGACCCCCGAGCAGTGGAAGAGCCACAGGTCCTACAGCTGCCAGGTGACCCACGAGGGCAGCACCGTGGAAAAGACCGTGGCCCCAACCGAGTGCAGC

Other antibodies of the invention include those where the amino acids ornucleic acids encoding the amino acids have been mutated, yet have atleast 60, 65, 70, 75, 80, 85, 90, or 95 percent identity to thesequences described in Table 1. Some embodiments include mutant aminoacid sequences wherein no more than 1, 2, 3, 4 or 5 amino acids havebeen mutated in the variable regions when compared with the variableregions depicted in the sequence described in Table 1, while retainingsubstantially the same antigen binding activity.

Since each of these antibodies can bind to Factor P, the VH, VL, fulllength light chain, and full length heavy chain sequences (amino acidsequences and the nucleotide sequences encoding the amino acidsequences) can be “mixed and matched” to create other Factor P-bindingantibodies of the invention. Such “mixed and matched” Factor P-bindingantibodies can be tested using the binding assays known in the art(e.g., ELISAs, and other assays described in the Example section). Whenthese chains are mixed and matched, a VH sequence from a particularVH/VL pairing should be replaced with a structurally similar VHsequence. Likewise a full length heavy chain sequence from a particularfull length heavy chain/full length light chain pairing should bereplaced with a structurally similar full length heavy chain sequence.Likewise, a VL sequence from a particular VH/VL pairing should bereplaced with a structurally similar VL sequence. Likewise a full lengthlight chain sequence from a particular full length heavy chain/fulllength light chain pairing should be replaced with a structurallysimilar full length light chain sequence. Accordingly, in one aspect,the invention provides an isolated antibody or antigen binding regionthereof having: a heavy chain variable domain comprising an amino acidsequence selected from the group consisting of SEQ ID NOs: 7, 21, 35,49, 63, 77, 91, 105, 119, 133, 147, 161, 175, 189, 203, 217, 231, 245,259 and 273, and a light chain variable domain comprising an amino acidsequence selected from the group consisting of SEQ ID NOs: 8, 22, 36,50, 64, 78, 92, 106, 120, 134, 148, 162, 176, 190, 204, 218, 232, 246,260, and 274 wherein the antibody specifically binds to Factor P (e.g.,human and/or cynomolgus Factor P).

In another aspect, the invention provides (i) an isolated antibodyhaving: a full length heavy chain comprising an amino acid sequence thathas been optimized for expression in a mammalian cell selected from thegroup consisting of SEQ ID NOs: 9, 23, 37, 51, 65, 79, 93, 107, 121,135, 149, 163, 177, 191, 205, 219, 233, 247, 261 and 275, and a fulllength light chain comprising an amino acid sequence that has beenoptimized for expression in a mammalian cell selected from the groupconsisting of SEQ ID NOs: 10, 24, 38, 52, 66, 80, 94, 108, 122, 136,150, 164, 178, 192, 206, 220, 234, 248, 262 and 276; or (ii) afunctional protein comprising an antigen binding portion thereof.

The terms “complementarity determining region,” and “CDR,” as usedherein refer to the sequences of amino acids within antibody variableregions which confer antigen specificity and binding affinity. Ingeneral, there are three CDRs in each heavy chain variable region(HCDR1, HCDR2, HCDR3) and three CDRs in each light chain variable region(LCDR1, LCDR2, LCDR3).

The precise amino acid sequence boundaries of a given CDR can be readilydetermined using any of a number of well-known schemes, including thosedescribed by Kabat et al. (1991), “Sequences of Proteins ofImmunological Interest,” 5th Ed. Public Health Service, NationalInstitutes of Health, Bethesda, Md. (“Kabat” numbering scheme),Al-Lazikani et al., (1997) JMB 273, 927-948 (“Chothia” numberingscheme).

For example, under Kabat, the CDR amino acid residues in the heavy chainvariable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2), and95-102 (HCDR3); and the CDR amino acid residues in the light chainvariable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2), and89-97 (LCDR3). Under Chothia the CDR amino acids in the VH are numbered26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3); and the amino acidresidues in VL are numbered 26-32 (LCDR1), 50-52 (LCDR2), and 91-96(LCDR3). By combining the CDR definitions of both Kabat and Chothia, theCDRs consist of amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and95-102 (HCDR3) in human VH and amino acid residues 24-34 (LCDR1), 50-56(LCDR2), and 89-97 (LCDR3) in human VL.

In another aspect, the present invention provides Factor P bindingantibodies that comprise the heavy chain and light chain CDR1s, CDR2s,and CDR3s as described in Table 1, or combinations thereof. The aminoacid sequences of the VH CDR1 s of the antibodies are shown in SEQ IDNOs: 1, 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155, 169, 183, 197,211, 225, 239, 253, or 267. The amino acid sequences of the VH CDR2s ofthe antibodies and are shown in SEQ ID NOs: 2, 16, 30, 44, 58, 72, 86,100, 114, 128, 142, 156, 170, 184, 198, 212, 226, 240, 254, or 268. Theamino acid sequences of the VH CDR3s of the antibodies are shown in SEQID NOs: 3, 17, 31, 45, 59, 73, 87, 101, 115, 129, 143, 157, 171, 185,199, 213, 227, 241, 255, or 269. The amino acid sequences of the VLCDR1s of the antibodies are shown in SEQ ID NOs: 4, 18, 32, 46, 60, 74,88, 102, 116, 130, 144, 158, 172, 186, 200, 214, 228, 242, 256, or 270.The amino acid sequences of the VL CDR2s of the antibodies are shown inSEQ ID NOs: 5, 19, 33, 47, 61, 75, 89, 103, 117, 131, 145, 159, 173,187, 201, 215, 229, 243, 257, or 271. The amino acid sequences of the VLCDR3s of the antibodies are shown in SEQ ID NOs: 6, 20, 34, 48, 62, 76,90, 104, 118, 132, 146, 160, 174, 188, 202, 216, 230, 244, 258, or 272.These CDR regions are delineated using the Kabat system.

Alternatively, as defined using the Chothia system (Al-Lazikani et al.,(1997) JMB 273, 927-948) the amino acid sequences of the VH CDR1s of theantibodies are shown in SEQ ID NOs: 281, 287, 293, 299, 305, 311, 317,323, 329, 335, 341, 347, 353, 359, 365, 371, 377, 383, 389, or 395. Theamino acid sequences of the VH CDR2s of the antibodies and are shown inSEQ ID NOs: 282, 288, 294, 300, 306, 312, 318, 324, 330, 336, 342, 348,354, 360, 366, 372, 378, 384, 390, or 396. The amino acid sequences ofthe VH CDR3s of the antibodies are shown in SEQ ID NOs: 283, 289, 295,301, 307, 313, 319, 325, 331, 337, 343, 349, 355, 361, 367, 373, 379,385, 391, or 397. The amino acid sequences of the VL CDR1s of theantibodies are shown in SEQ ID NOs: 284, 290, 296, 302, 308, 314, 320,326, 332, 338, 344, 350, 356, 362, 368, 374, 380, 386, 392, or 398. Theamino acid sequences of the VL CDR2s of the antibodies are shown in SEQID NOs: 285, 291, 297, 303, 309, 315, 321, 327, 333, 339, 345, 351, 357,363, 369, 375, 381, 387, 393, or 399. The amino acid sequences of the VLCDR3s of the antibodies are shown in SEQ ID NOs: 286, 292, 298, 304,310, 316, 322, 328, 334, 340, 346, 352, 358, 364, 370, 376, 382, 388,394, or 400.

Given that each of these antibodies can bind to Factor P and thatantigen-binding specificity is provided primarily by the CDR1, 2 and 3regions, the VH CDR1, 2 and 3 sequences and VL CDR1, 2 and 3 sequencescan be “mixed and matched” (i.e., CDRs from different antibodies can bemixed and matched, although each antibody preferably contains a VH CDR1,2 and 3 and a VL CDR1, 2 and 3 to create other Factor P binding bindingmolecules of the invention. Such “mixed and matched” Factor P bindingantibodies can be tested using the binding assays known in the art andthose described in the Examples (e.g., ELISAs, SET, Biacore). When VHCDR sequences are mixed and matched, the CDR1, CDR2 and/or CDR3 sequencefrom a particular VH sequence should be replaced with a structurallysimilar CDR sequence(s). Likewise, when VL CDR sequences are mixed andmatched, the CDR1, CDR2 and/or CDR3 sequence from a particular VLsequence should be replaced with a structurally similar CDR sequence(s).It will be readily apparent to the ordinarily skilled artisan that novelVH and VL sequences can be created by substituting one or more VH and/orVL CDR region sequences with structurally similar sequences from the CDRsequences shown herein for monoclonal antibodies of the presentinvention. In addition to the foregoing, in one embodiment, the antigenbinding fragments of the antibodies described herein can comprise a VHCDR1, 2, and 3, or a VL CDR 1, 2, and 3, wherein the fragment binds toFactor P as a single variable domain.

In certain embodiments of the invention, the antibodies or antigenbinding fragments thereof may have the heavy and light chain sequencesof the Fabs described in Table 1. More specifically, the antibody orantigen binding fragment thereof may have the heavy and light sequenceof Fab NVS962, NVS963, NVS964, NVS965, NVS966, NVS967, NVS805, NVS806,NVS807, NVS808, NVS809, NVS962-S, NVS962-Q, NVS962-S31A, NVS962-G,NVS962-T, NVS965-S, NVS965-T, or NVS965-Q.

In other embodiments of the invention the antibody or antigen bindingfragment in that specifically binds Factor P comprises a heavy chainvariable region CDR1, a heavy chain variable region CDR2, a heavy chainvariable region CDR3, a light chain variable region CDR1, a light chainvariable region CDR2, and a light chain variable region CDR3 as definedby Kabat and described in Table 1. In still other embodiments of theinvention the antibody or antigen binding fragment in that specificallybinds Factor P comprises a heavy chain variable region CDR1, a heavychain variable region CDR2, a heavy chain variable region CDR3, a lightchain variable region CDR1, a light chain variable region CDR2, and alight chain variable region CDR3 as defined by Chothia and described inTable 1.

In a specific embodiment, the invention includes an antibody thatspecifically binds to Factor P comprising a heavy chain variable regionCDR1 of SEQ ID NO:1; a heavy chain variable region CDR2 of SEQ ID NO: 2;a heavy chain variable region CDR3 of SEQ ID NO: 3; a light chainvariable region CDR1 of SEQ ID NO: 4; a light chain variable region CDR2of SEQ ID NO: 5; and a light chain variable region CDR3 of SEQ ID NO: 6.In another specific embodiment, the invention includes an antibody thatspecifically binds to Factor P comprising a heavy chain variable regionCDR1 of SEQ ID NO: 15; a heavy chain variable region CDR2 of SEQ ID NO:16; a heavy chain variable region CDR3 of SEQ ID NO: 17; a light chainvariable region CDR1 of SEQ ID NO: 18; a light chain variable regionCDR2 of SEQ ID NO: 19; and a light chain variable region CDR3 of SEQ IDNO: 20. In another specific embodiment, the invention includes anantibody that specifically binds to Factor P comprising a heavy chainvariable region CDR1 of SEQ ID NO: 29; a heavy chain variable regionCDR2 of SEQ ID NO: 30; a heavy chain variable region CDR3 of SEQ ID NO:31; a light chain variable region CDR1 of SEQ ID NO: 32; a light chainvariable region CDR2 of SEQ ID NO: 33; and a light chain variable regionCDR3 of SEQ ID NO: 34. In another specific embodiment, the inventionincludes an antibody that specifically binds to Factor P comprising aheavy chain variable region CDR1 of SEQ ID NO: 43; a heavy chainvariable region CDR2 of SEQ ID NO: 44; a heavy chain variable regionCDR3 of SEQ ID NO: 45; a light chain variable region CDR1 of SEQ ID NO:46; a light chain variable region CDR2 of SEQ ID NO: 47; and a lightchain variable region CDR3 of SEQ ID NO: 48. In another specificembodiment, the invention includes an antibody that specifically bindsto Factor P comprising a heavy chain variable region CDR1 of SEQ ID NO:57; a heavy chain variable region CDR2 of SEQ ID NO: 58; a heavy chainvariable region CDR3 of SEQ ID NO: 59; a light chain variable regionCDR1 of SEQ ID NO: 60; a light chain variable region CDR2 of SEQ ID NO:61; and a light chain variable region CDR3 of SEQ ID NO: 62. In anotherspecific embodiment, the invention includes an antibody thatspecifically binds to Factor P comprising a heavy chain variable regionCDR1 of SEQ ID NO: 71; a heavy chain variable region CDR2 of SEQ ID NO:72; a heavy chain variable region CDR3 of SEQ ID NO: 73; a light chainvariable region CDR1 of SEQ ID NO: 74; a light chain variable regionCDR2 of SEQ ID NO: 75; and a light chain variable region CDR3 of SEQ IDNO: 76. In another specific embodiment, the invention includes anantibody that specifically binds to Factor P comprising a heavy chainvariable region CDR1 of SEQ ID NO: 85; a heavy chain variable regionCDR2 of SEQ ID NO: 86; a heavy chain variable region CDR3 of SEQ ID NO:87; a light chain variable region CDR1 of SEQ ID NO: 88; a light chainvariable region CDR2 of SEQ ID NO: 89; and a light chain variable regionCDR3 of SEQ ID NO: 90. In another specific embodiment, the inventionincludes an antibody that specifically binds to Factor P comprising aheavy chain variable region CDR1 of SEQ ID NO: 99; a heavy chainvariable region CDR2 of SEQ ID NO: 100; a heavy chain variable regionCDR3 of SEQ ID NO: 101; a light chain variable region CDR1 of SEQ ID NO:102; a light chain variable region CDR2 of SEQ ID NO: 103; and a lightchain variable region CDR3 of SEQ ID NO: 104. In another specificembodiment, the invention includes an antibody that specifically bindsto Factor P comprising a heavy chain variable region CDR1 of SEQ ID NO:113; a heavy chain variable region CDR2 of SEQ ID NO: 114; a heavy chainvariable region CDR3 of SEQ ID NO: 115; a light chain variable regionCDR1 of SEQ ID NO: 116; a light chain variable region CDR2 of SEQ ID NO:117; and a light chain variable region CDR3 of SEQ ID NO: 118. Inanother specific embodiment, the invention includes an antibody thatspecifically binds to Factor P comprising a heavy chain variable regionCDR1 of SEQ ID NO: 127; a heavy chain variable region CDR2 of SEQ ID NO:128; a heavy chain variable region CDR3 of SEQ ID NO: 129; a light chainvariable region CDR1 of SEQ ID NO: 130; a light chain variable regionCDR2 of SEQ ID NO: 131; and a light chain variable region CDR3 of SEQ IDNO: 132. In another specific embodiment, the invention includes anantibody that specifically binds to Factor P comprising a heavy chainvariable region CDR1 of SEQ ID NO: 141; a heavy chain variable regionCDR2 of SEQ ID NO: 142; a heavy chain variable region CDR3 of SEQ ID NO:143; a light chain variable region CDR1 of SEQ ID NO: 144; a light chainvariable region CDR2 of SEQ ID NO: 145; and a light chain variableregion CDR3 of SEQ ID NO: 146. In another specific embodiment, theinvention includes an antibody that specifically binds to Factor Pcomprising a heavy chain variable region CDR1 of SEQ ID NO: 155; a heavychain variable region CDR2 of SEQ ID NO: 156; a heavy chain variableregion CDR3 of SEQ ID NO: 157; a light chain variable region CDR1 of SEQID NO: 158; a light chain variable region CDR2 of SEQ ID NO: 159; and alight chain variable region CDR3 of SEQ ID NO: 160. In another specificembodiment, the invention includes an antibody that specifically bindsto Factor P comprising a heavy chain variable region CDR1 of SEQ ID NO:169; a heavy chain variable region CDR2 of SEQ ID NO: 170; a heavy chainvariable region CDR3 of SEQ ID NO: 171; a light chain variable regionCDR1 of SEQ ID NO: 172; a light chain variable region CDR2 of SEQ ID NO:173; and a light chain variable region CDR3 of SEQ ID NO: 174. Inanother specific embodiment, the invention includes an antibody thatspecifically binds to Factor P comprising a heavy chain variable regionCDR1 of SEQ ID NO: 183; a heavy chain variable region CDR2 of SEQ ID NO:184; a heavy chain variable region CDR3 of SEQ ID NO: 185; a light chainvariable region CDR1 of SEQ ID NO: 186; a light chain variable regionCDR2 of SEQ ID NO: 187; and a light chain variable region CDR3 of SEQ IDNO: 188. In another specific embodiment, the invention includes anantibody that specifically binds to Factor P comprising a heavy chainvariable region CDR1 of SEQ ID NO: 197; a heavy chain variable regionCDR2 of SEQ ID NO: 198; a heavy chain variable region CDR3 of SEQ ID NO:199; a light chain variable region CDR1 of SEQ ID NO: 200; a light chainvariable region CDR2 of SEQ ID NO: 201; and a light chain variableregion CDR3 of SEQ ID NO: 202. In another specific embodiment, theinvention includes an antibody that specifically binds to Factor Pcomprising a heavy chain variable region CDR1 of SEQ ID NO: 211; a heavychain variable region CDR2 of SEQ ID NO: 212; a heavy chain variableregion CDR3 of SEQ ID NO: 213; a light chain variable region CDR1 of SEQID NO: 214; a light chain variable region CDR2 of SEQ ID NO: 215; and alight chain variable region CDR3 of SEQ ID NO: 216. In another specificembodiment, the invention includes an antibody that specifically bindsto Factor P comprising a heavy chain variable region CDR1 of SEQ ID NO:225; a heavy chain variable region CDR2 of SEQ ID NO: 226; a heavy chainvariable region CDR3 of SEQ ID NO: 227; a light chain variable regionCDR1 of SEQ ID NO: 228; a light chain variable region CDR2 of SEQ ID NO:229; and a light chain variable region CDR3 of SEQ ID NO: 230. Inanother specific embodiment, the invention includes an antibody thatspecifically binds to Factor P comprising a heavy chain variable regionCDR1 of SEQ ID NO: 239; a heavy chain variable region CDR2 of SEQ ID NO:240; a heavy chain variable region CDR3 of SEQ ID NO: 241; a light chainvariable region CDR1 of SEQ ID NO: 242; a light chain variable regionCDR2 of SEQ ID NO: 243; and a light chain variable region CDR3 of SEQ IDNO: 244. In another specific embodiment, the invention includes anantibody that specifically binds to Factor P comprising a heavy chainvariable region CDR1 of SEQ ID NO: 253; a heavy chain variable regionCDR2 of SEQ ID NO: 254; a heavy chain variable region CDR3 of SEQ ID NO:255; a light chain variable region CDR1 of SEQ ID NO: 256; a light chainvariable region CDR2 of SEQ ID NO: 257; and a light chain variableregion CDR3 of SEQ ID NO: 258. In another specific embodiment, theinvention includes an antibody that specifically binds to Factor Pcomprising a heavy chain variable region CDR1 of SEQ ID NO: 267; a heavychain variable region CDR2 of SEQ ID NO: 268; a heavy chain variableregion CDR3 of SEQ ID NO: 269; a light chain variable region CDR1 of SEQID NO: 270; a light chain variable region CDR2 of SEQ ID NO: 271; and alight chain variable region CDR3 of SEQ ID NO: 271.

In another specific embodiment, the invention includes an antibody thatspecifically binds to Factor P comprising a heavy chain variable regionCDR1 of SEQ ID NO: 281; a heavy chain variable region CDR2 of SEQ ID NO:282; a heavy chain variable region CDR3 of SEQ ID NO: 283; a light chainvariable region CDR1 of SEQ ID NO: 284; a light chain variable regionCDR2 of SEQ ID NO: 285; and a light chain variable region CDR3 of SEQ IDNO: 286. In another specific embodiment, the invention includes anantibody that specifically binds to Factor P comprising a heavy chainvariable region CDR1 of SEQ ID NO: 287; a heavy chain variable regionCDR2 of SEQ ID NO: 288; a heavy chain variable region CDR3 of SEQ ID NO:289; a light chain variable region CDR1 of SEQ ID NO: 290; a light chainvariable region CDR2 of SEQ ID NO: 291; and a light chain variableregion CDR3 of SEQ ID NO: 292. In another specific embodiment, theinvention includes an antibody that specifically binds to Factor Pcomprising a heavy chain variable region CDR1 of SEQ ID NO: 293; a heavychain variable region CDR2 of SEQ ID NO: 294; a heavy chain variableregion CDR3 of SEQ ID NO: 295; a light chain variable region CDR1 of SEQID NO: 296; a light chain variable region CDR2 of SEQ ID NO: 297; and alight chain variable region CDR3 of SEQ ID NO: 298. In another specificembodiment, the invention includes an antibody that specifically bindsto Factor P comprising a heavy chain variable region CDR1 of SEQ ID NO:299; a heavy chain variable region CDR2 of SEQ ID NO: 300; a heavy chainvariable region CDR3 of SEQ ID NO: 301; a light chain variable regionCDR1 of SEQ ID NO: 302; a light chain variable region CDR2 of SEQ ID NO:303; and a light chain variable region CDR3 of SEQ ID NO: 304. Inanother specific embodiment, the invention includes an antibody thatspecifically binds to Factor P comprising a heavy chain variable regionCDR1 of SEQ ID NO: 305; a heavy chain variable region CDR2 of SEQ ID NO:306; a heavy chain variable region CDR3 of SEQ ID NO: 307; a light chainvariable region CDR1 of SEQ ID NO: 308; a light chain variable regionCDR2 of SEQ ID NO: 309; and a light chain variable region CDR3 of SEQ IDNO: 310. In another specific embodiment, the invention includes anantibody that specifically binds to Factor P comprising a heavy chainvariable region CDR1 of SEQ ID NO: 311; a heavy chain variable regionCDR2 of SEQ ID NO: 312; a heavy chain variable region CDR3 of SEQ ID NO:313; a light chain variable region CDR1 of SEQ ID NO: 314; a light chainvariable region CDR2 of SEQ ID NO: 315; and a light chain variableregion CDR3 of SEQ ID NO: 316. In another specific embodiment, theinvention includes an antibody that specifically binds to Factor Pcomprising a heavy chain variable region CDR1 of SEQ ID NO: 317; a heavychain variable region CDR2 of SEQ ID NO: 318; a heavy chain variableregion CDR3 of SEQ ID NO: 319; a light chain variable region CDR1 of SEQID NO: 320; a light chain variable region CDR2 of SEQ ID NO: 321; and alight chain variable region CDR3 of SEQ ID NO: 322. In another specificembodiment, the invention includes an antibody that specifically bindsto Factor P comprising a heavy chain variable region CDR1 of SEQ ID NO:323; a heavy chain variable region CDR2 of SEQ ID NO: 324; a heavy chainvariable region CDR3 of SEQ ID NO: 325; a light chain variable regionCDR1 of SEQ ID NO: 326; a light chain variable region CDR2 of SEQ ID NO:327; and a light chain variable region CDR3 of SEQ ID NO: 328. Inanother specific embodiment, the invention includes an antibody thatspecifically binds to Factor P comprising a heavy chain variable regionCDR1 of SEQ ID NO: 329; a heavy chain variable region CDR2 of SEQ ID NO:330; a heavy chain variable region CDR3 of SEQ ID NO: 331; a light chainvariable region CDR1 of SEQ ID NO: 332; a light chain variable regionCDR2 of SEQ ID NO: 333; and a light chain variable region CDR3 of SEQ IDNO: 334. In another specific embodiment, the invention includes anantibody that specifically binds to Factor P comprising a heavy chainvariable region CDR1 of SEQ ID NO: 335; a heavy chain variable regionCDR2 of SEQ ID NO: 336; a heavy chain variable region CDR3 of SEQ ID NO:337; a light chain variable region CDR1 of SEQ ID NO: 338; a light chainvariable region CDR2 of SEQ ID NO: 339; and a light chain variableregion CDR3 of SEQ ID NO: 340. In another specific embodiment, theinvention includes an antibody that specifically binds to Factor Pcomprising a heavy chain variable region CDR1 of SEQ ID NO: 341; a heavychain variable region CDR2 of SEQ ID NO: 342; a heavy chain variableregion CDR3 of SEQ ID NO: 343; a light chain variable region CDR1 of SEQID NO: 344; a light chain variable region CDR2 of SEQ ID NO: 345; and alight chain variable region CDR3 of SEQ ID NO: 346. In another specificembodiment, the invention includes an antibody that specifically bindsto Factor P comprising a heavy chain variable region CDR1 of SEQ ID NO:347; a heavy chain variable region CDR2 of SEQ ID NO: 348; a heavy chainvariable region CDR3 of SEQ ID NO: 349; a light chain variable regionCDR1 of SEQ ID NO: 350; a light chain variable region CDR2 of SEQ ID NO:351; and a light chain variable region CDR3 of SEQ ID NO: 352. Inanother specific embodiment, the invention includes an antibody thatspecifically binds to Factor P comprising a heavy chain variable regionCDR1 of SEQ ID NO: 353; a heavy chain variable region CDR2 of SEQ ID NO:354; a heavy chain variable region CDR3 of SEQ ID NO: 355; a light chainvariable region CDR1 of SEQ ID NO: 356; a light chain variable regionCDR2 of SEQ ID NO: 357; and a light chain variable region CDR3 of SEQ IDNO: 358. In another specific embodiment, the invention includes anantibody that specifically binds to Factor P comprising a heavy chainvariable region CDR1 of SEQ ID NO: 359; a heavy chain variable regionCDR2 of SEQ ID NO: 360; a heavy chain variable region CDR3 of SEQ ID NO:361; a light chain variable region CDR1 of SEQ ID NO: 362; a light chainvariable region CDR2 of SEQ ID NO: 363; and a light chain variableregion CDR3 of SEQ ID NO: 364. In another specific embodiment, theinvention includes an antibody that specifically binds to Factor Pcomprising a heavy chain variable region CDR1 of SEQ ID NO: 365; a heavychain variable region CDR2 of SEQ ID NO: 366; a heavy chain variableregion CDR3 of SEQ ID NO: 367; a light chain variable region CDR1 of SEQID NO: 368; a light chain variable region CDR2 of SEQ ID NO: 369; and alight chain variable region CDR3 of SEQ ID NO: 370. In another specificembodiment, the invention includes an antibody that specifically bindsto Factor P comprising a heavy chain variable region CDR1 of SEQ ID NO:371; a heavy chain variable region CDR2 of SEQ ID NO: 372; a heavy chainvariable region CDR3 of SEQ ID NO: 373; a light chain variable regionCDR1 of SEQ ID NO: 374; a light chain variable region CDR2 of SEQ ID NO:375; and a light chain variable region CDR3 of SEQ ID NO: 376. Inanother specific embodiment, the invention includes an antibody thatspecifically binds to Factor P comprising a heavy chain variable regionCDR1 of SEQ ID NO: 377; a heavy chain variable region CDR2 of SEQ ID NO:378; a heavy chain variable region CDR3 of SEQ ID NO: 379; a light chainvariable region CDR1 of SEQ ID NO: 380; a light chain variable regionCDR2 of SEQ ID NO: 381; and a light chain variable region CDR3 of SEQ IDNO: 382. In another specific embodiment, the invention includes anantibody that specifically binds to Factor P comprising a heavy chainvariable region CDR1 of SEQ ID NO: 383; a heavy chain variable regionCDR2 of SEQ ID NO: 384; a heavy chain variable region CDR3 of SEQ ID NO:385; a light chain variable region CDR1 of SEQ ID NO: 386; a light chainvariable region CDR2 of SEQ ID NO: 387; and a light chain variableregion CDR3 of SEQ ID NO: 388. In another specific embodiment, theinvention includes an antibody that specifically binds to Factor Pcomprising a heavy chain variable region CDR1 of SEQ ID NO: 389; a heavychain variable region CDR2 of SEQ ID NO: 390; a heavy chain variableregion CDR3 of SEQ ID NO: 391; a light chain variable region CDR1 of SEQID NO: 392; a light chain variable region CDR2 of SEQ ID NO: 393; and alight chain variable region CDR3 of SEQ ID NO: 394. In another specificembodiment, the invention includes an antibody that specifically bindsto Factor P comprising a heavy chain variable region CDR1 of SEQ ID NO:395; a heavy chain variable region CDR2 of SEQ ID NO: 396; a heavy chainvariable region CDR3 of SEQ ID NO: 397; a light chain variable regionCDR1 of SEQ ID NO: 398; a light chain variable region CDR2 of SEQ ID NO:399; and a light chain variable region CDR3 of SEQ ID NO: 400.

In certain embodiments, the invention includes antibodies or antigenbinding fragments that specifically binds to Factor P as described inTable 1. In a preferred embodiment, the antibody, or antigen bindingfragment, that binds Factor P is Fab NVS962, NVS963, NVS964, NVS965,NVS966, NVS967, NVS804, NVS805, NVS806, NVS807, NVS808, NVS809,NVS962-S, NVS962-Q, NVS962-G, NVS962-T, NVS962-S31A, NVS965-T, NVS965-Q,or NVS965-S.

As used herein, a human antibody comprises heavy or light chain variableregions or full length heavy or light chains that are “the product of”or “derived from” a particular germline sequence if the variable regionsor full length chains of the antibody are obtained from a system thatuses human germline immunoglobulin genes. Such systems includeimmunizing a transgenic mouse carrying human immunoglobulin genes withthe antigen of interest or screening a human immunoglobulin gene librarydisplayed on phage with the antigen of interest. A human antibody thatis “the product of” or “derived from” a human germline immunoglobulinsequence can be identified as such by comparing the amino acid sequenceof the human antibody to the amino acid sequences of human germlineimmunoglobulins and selecting the human germline immunoglobulin sequencethat is closest in sequence (i.e., greatest % identity) to the sequenceof the human antibody. A human antibody that is “the product of” or“derived from” a particular human germline immunoglobulin sequence maycontain amino acid differences as compared to the germline sequence, dueto, for example, naturally occurring somatic mutations or intentionalintroduction of site-directed mutations. However, in the VH or VLframework regions, a selected human antibody typically is at least 90%identical in amino acids sequence to an amino acid sequence encoded by ahuman germline immunoglobulin gene and contains amino acid residues thatidentify the human antibody as being human when compared to the germlineimmunoglobulin amino acid sequences of other species (e.g., murinegermline sequences). In certain cases, a human antibody may be at least60%, 70%, 80%, 90%, or at least 95%, or even at least 96%, 97%, 98%, or99% identical in amino acid sequence to the amino acid sequence encodedby the germline immunoglobulin gene. Typically, a recombinant humanantibody will display no more than 10 amino acid differences from theamino acid sequence encoded by the human germline immunoglobulin gene inthe VH or VL framework regions. In certain cases, the human antibody maydisplay no more than 5, or even no more than 4, 3, 2, or 1 amino aciddifference from the amino acid sequence encoded by the germlineimmunoglobulin gene. Examples of human germline immunoglobulin genesinclude, but are not limited to the variable domain germline fragmentsdescribed below, as well as DP47 and DPK9.

Homologous Antibodies

In yet another embodiment, the present invention provides an antibody,or an antigen binding fragment thereof, comprising amino acid sequencesthat are homologous to the sequences described in Table 1, and theantibody binds to a Factor P protein (e.g., human and/or cynomolgusFactor P), and retains the desired functional properties of thoseantibodies described in Table 1.

For example, the invention provides an isolated antibody, or afunctional antigen binding fragment thereof, comprising a heavy chainvariable domain and a light chain variable domain, wherein the heavychain variable domain comprises an amino acid sequence that is at least80%, at least 90%, or at least 95% identical to an amino acid sequenceselected from the group consisting of SEQ ID NOs: 7, 21, 35, 49, 63, 77,91, 105, 119, 133, 147, 161, 175, 189, 203, 217, 231, 245, 259 and 273;the light chain variable domain comprises an amino acid sequence that isat least 80%, at least 90%, or at least 95% identical to an amino acidsequence selected from the group consisting of SEQ ID NOs: 8, 22, 36,50, 64, 78, 92, 106, 120, 134, 148, 162, 176, 190, 204, 218, 232, 246,260, and 274; and the antibody specifically binds to Factor P (e.g.,human and/or cynomolgus Factor P).

In other embodiments, the VH and/or VL amino acid sequences may be 50%,60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to the sequencesset forth in Table 1. In other embodiments, the VH and/or VL amino acidsequences may be identical except for an amino acid substitution in nomore than 1, 2, 3, 4 or 5 amino acid positions. An antibody having VHand VL regions having high (i. e., 80% or greater) identity to the VHand VL regions of those described in Table 1 can be obtained bymutagenesis (e.g., site-directed or PCR-mediated mutagenesis) of nucleicacid molecules encoding SEQ ID NOs: 7, 21, 35, 49, 63, 77, 91, 105, 119,133, 147, 161, 175, 189, 203, 217, 231, 245, 259 or 273 and SEQ ID NOs:8, 22, 36, 50, 64, 78, 92, 106, 120, 134, 148, 162, 176, 190, 204, 218,232, 246, 260, or 274, respectively, followed by testing of the encodedaltered antibody for retained function using the functional assaysdescribed herein.

In other embodiments, the full length heavy chain and/or full lengthlight chain amino acid sequences may be 50% 60%, 70%, 80%, 90%, 95%,96%, 97%, 98% or 99% identical to the sequences set forth in Table 1. Anantibody having a full length heavy chain and full length light chainhaving high (i.e., 80% or greater) identity to the full length heavychains of any of SEQ ID NOs: 9, 23, 37, 51, 65, 79, 93, 107, 121, 135,149, 163, 177, 191, 205, 219, 233, 247, 261 or 275, and full lengthlight chains of any of SEQ ID NOs 10, 24, 38, 52, 66, 80, 94, 108, 122,136, 150, 164, 178, 192, 206, 220, 234, 248, 262, or 276, can beobtained by mutagenesis (e.g., site-directed or PCR-mediatedmutagenesis) of nucleic acid molecules encoding such polypeptides,followed by testing of the encoded altered antibody for retainedfunction using the functional assays described herein.

In other embodiments, the full length heavy chain and/or full lengthlight chain nucleotide sequences may be 60%, 70%, 80%, 90%, 95%, 96%,97%, 98% or 99% identical to the sequences set forth in Table 1.

In other embodiments, the variable regions of heavy chain and/or thevariable regions of light chain nucleotide sequences may be 60%, 70%,80%, 90%, 95%, 96%, 97%, 98% or 99% identical to the sequences set forthin Table 1.

As used herein, the percent identity between the two sequences is afunction of the number of identical positions shared by the sequences(i.e., % identity equals number of identical positions/total number ofpositions x 100), taking into account the number of gaps, and the lengthof each gap, which need to be introduced for optimal alignment of thetwo sequences. The comparison of sequences and determination of percentidentity between two sequences can be accomplished using a mathematicalalgorithm, as described in the non-limiting examples below.

Additionally or alternatively, the protein sequences of the presentinvention can further be used as a “query sequence” to perform a searchagainst public databases to, for example, identify related sequences.For example, such searches can be performed using the BLAST program(version 2.0) of Altschul, et al., 1990 J. Mol. Biol. 215:403-10.

Antibodies with Conservative Modifications

In certain embodiments, an antibody of the invention has a heavy chainvariable region comprising CDR1, CDR2, and CDR3 sequences and a lightchain variable region comprising CDR1, CDR2, and CDR3 sequences, whereinone or more of these CDR sequences have specified amino acid sequencesbased on the antibodies described herein or conservative modificationsthereof, and wherein the antibodies retain the desired functionalproperties of the Factor P-binding antibodies of the invention.Accordingly, the invention provides an isolated antibody, or a antigenbinding fragment thereof, consisting of a heavy chain variable regioncomprising CDR1, CDR2, and CDR3 sequences and a light chain variableregion comprising CDR1, CDR2, and CDR3 sequences, wherein: the heavychain variable region CDR1 amino acid sequences are selected from thegroup consisting of SEQ ID NOs: 1, 15, 29, 43, 57, 71, 85, 99, 113, 127,141, 155, 169, 183, 197, 211, 225, 239, 253, and 267, and conservativemodifications thereof; the heavy chain variable region CDR2 amino acidsequences are selected from the group consisting of SEQ ID NOs: 2, 16,30, 44, 58, 72, 86, 100, 114, 128, 142, 156, 170, 184, 198, 212, 226,240, 254, and 268, and conservative modifications thereof; the heavychain variable region CDR3 amino acid sequences are selected from thegroup consisting of SEQ ID NOs: 3, 17, 31, 45, 59, 73, 87, 101, 115,129, 143, 157, 171, 185, 199, 213, 227, 241, 255, and 269, andconservative modifications thereof; the light chain variable regionsCDR1 amino acid sequences are selected from the group consisting of SEQID NOs: 4, 18, 32, 46, 60, 74, 88, 102, 116, 130, 144, 158, 172, 186,200, 214, 228, 242, 256, and 270, and conservative modificationsthereof; the light chain variable regions CDR2 amino acid sequences areselected from the group consisting of SEQ ID NOs: 5, 19, 33, 47, 61, 75,89, 103, 117, 131, 145, 159, 173, 187, 201, 215, 229, 243, 257, and 271,and conservative modifications thereof; the light chain variable regionsof CDR3 amino acid sequences are selected from the group consisting ofSEQ ID NOs: 6, 20, 34, 48, 62, 76, 90, 104, 118, 132, 146, 160, 174,188, 202, 216, 230, 244, 258, and 272, and conservative modificationsthereof; and the antibody or antigen binding fragment thereofspecifically binds to Factor P.

In other embodiments, the antibody of the invention is optimized forexpression in a mammalian cell has a full length heavy chain sequenceand a full length light chain sequence, wherein one or more of thesesequences have specified amino acid sequences based on the antibodiesdescribed herein or conservative modifications thereof, and wherein theantibodies retain the desired functional properties of the Factor Pbinding antibodies of the invention. Accordingly, the invention providesan isolated antibody optimized for expression in a mammalian cellconsisting of a full length heavy chain and a full length light chainwherein the full length heavy chain has amino acid sequences selectedfrom the group of SEQ ID NOs: 9, 23, 37, 51, 65, 79, 93, 107, 121, 135,149, 163, 177, 191, 205, 219, 233, 247, 261 and 275, and conservativemodifications thereof; and the full length light chain has amino acidsequences selected from the group of SEQ ID NOs: 10, 24, 38, 52, 66, 80,94, 108, 122, 136, 150, 164, 178, 192, 206, 220, 234, 248, 262, and 276,and conservative modifications thereof; and the antibody specificallybinds to Factor P (e.g., human and/or cynomolgus Factor P).

Antibodies that Bind to the Same Epitope

The present invention provides antibodies that bind to the same epitopeas the Factor P binding antibodies described in Table 1. Additionalantibodies can therefore be identified based on their ability to compete(e.g., to competitively inhibit the binding of, in a statisticallysignificant manner) with other antibodies of the invention in Factor Pbinding assays (such as those described in the Examples). The ability ofa test antibody to inhibit the binding of antibodies of the presentinvention to a Factor P protein demonstrates that the test antibody cancompete with that antibody for binding to Factor P; such an antibodymay, according to non-limiting theory, bind to the same or a related(e.g., a structurally similar or spatially proximal) epitope on theFactor P protein as the antibody with which it competes. In a certainembodiment, the antibody that binds to the same epitope on Factor P asthe antibodies of the present invention is a human monoclonal antibody.Such human monoclonal antibodies can be prepared and isolated asdescribed herein. As used herein, an antibody “competes” for bindingwhen the competing antibody inhibits Factor P binding of an antibody orantigen binding fragment of the invention by more than 50%, in thepresence of an equimolar concentration of competing antibody.

In other embodiments the antibodies or antigen binding fragments of theinvention bind the Thrombospondin type 5 repeat (TSR 5) domain of FactorP (SEQ ID NO: 406). In other embodiments the antibodies or antigenbinding fragments of the invention bind a region of the Factor P TSR5domain comprising SEQ ID NO: 407. Still in other embodiments the regioncomprises SEQ ID NO: 408.

In other embodiments of the invention the isolated antibodies or antigenbinding fragments bind an epitope comprising SEQ ID NO: 407, and inother embodiments the epitope comprises SEQ ID NO: 408. In otherembodiments of the invention, the antibodies or antigen bindingfragments bind a peptide according to SEQ ID NO: 407 and in still otherembodiments the Factor P epitope includes SEQ ID NO: 408.

Engineered and Modified Antibodies

An antibody of the invention further can be prepared using an antibodyhaving one or more of the VH and/or VL sequences shown herein asstarting material to engineer a modified antibody, which modifiedantibody may have altered properties from the starting antibody. Anantibody can be engineered by modifying one or more residues within oneor both variable regions (i. e., VH and/or VL), for example within oneor more CDR regions and/or within one or more framework regions.Additionally or alternatively, an antibody can be engineered bymodifying residues within the constant region(s), for example to alterthe effector function(s) of the antibody.

One type of variable region engineering that can be performed is CDRgrafting. Antibodies interact with target antigens predominantly throughamino acid residues that are located in the six heavy and light chaincomplementarity determining regions (CDRs). For this reason, the aminoacid sequences within CDRs are more diverse between individualantibodies than sequences outside of CDRs. Because CDR sequences areresponsible for most antibody-antigen interactions, it is possible toexpress recombinant antibodies that mimic the properties of specificnaturally occurring antibodies by constructing expression vectors thatinclude CDR sequences from the specific naturally occurring antibodygrafted onto framework sequences from a different antibody withdifferent properties (see, e.g., Riechmann, L. et al., 1998 Nature332:323-327; Jones, P. et al., 1986 Nature 321:522-525; Queen, C. etal., 1989 Proc. Natl. Acad., U.S.A. 86:10029-10033; U.S. Pat. No.5,225,539 to Winter, and U.S. Pat. Nos. 5,530,101; 5,585,089; 5,693,762and 6,180,370 to Queen et al.)

Accordingly, another embodiment of the invention pertains to an isolatedantibody, or an antigen binding fragment thereof, comprising a heavychain variable region comprising CDR1 sequences having an amino acidsequence selected from the group consisting of SEQ ID NOs: 1, 15, 29,43, 57, 71, 85, 99, 113, 127, 141, 155, 169, 183, 197, 211, 225, 239,253, and 267; CDR2 sequences having an amino acid sequence selected fromthe group consisting of SEQ ID NOs: 2, 16, 30, 44, 58, 72, 86, 100, 114,128, 142, 156, 170, 184, 198, 212, 226, 240, 254, and 268; CDR3sequences having an amino acid sequence selected from the groupconsisting of SEQ ID NOs: 3, 17, 31, 45, 59, 73, 87, 101, 115, 129, 143,157, 171, 185, 199, 213, 227, 241, 255, and 269, respectively; and alight chain variable region having CDR1 sequences having an amino acidsequence selected from the group consisting of SEQ ID NOs: 4, 18, 32,46, 60, 74, 88, 102, 116, 130, 144, 158, 172, 186, 200, 214, 228, 242,256, and 270; CDR2 sequences having an amino acid sequence selected fromthe group consisting of SEQ ID NOs: 5, 19, 33, 47, 61, 75, 89, 103, 117,131, 145, 159, 173, 187, 201, 215, 229, 243, 257, and 271; and CDR3sequences consisting of an amino acid sequence selected from the groupconsisting of SEQ ID NOs: 6, 20, 34, 48, 62, 76, 90, 104, 118, 132, 146,160, 174, 188, 202, 216, 230, 244, 258, and 272, respectively. Thus,such antibodies contain the VH and VL CDR sequences of monoclonalantibodies, yet may contain different framework sequences from theseantibodies.

Alternatively, another embodiment of the invention pertains to anisolated antibody, or an antigen binding fragment thereof, comprising aheavy chain variable region comprising CDR1 sequences having an aminoacid sequence selected from the group consisting of SEQ ID NOs: 281,287, 293, 299, 305, 311, 317, 323, 329, 335, 341, 347, 353, 359, 365,371, 377, 383, 389, and 395; CDR2 sequences having an amino acidsequence selected from the group consisting of SEQ ID NOs: 282, 288,294, 300, 306, 312, 318, 324, 330, 336, 342, 348, 354, 360, 366, 372,378, 384, 390, and 396; CDR3 sequences having an amino acid sequenceselected from the group consisting of SEQ ID NOs: 283, 289, 295, 301,307, 313, 319, 325, 331, 337, 343, 349, 355, 361, 367, 373, 379, 385,391, and 397, respectively; and a light chain variable region havingCDR1 sequences having an amino acid sequence selected from the groupconsisting of SEQ ID NOs: 284, 290, 296, 302, 308, 314, 320, 326, 332,338, 344, 350, 356, 362, 368, 374, 380, 386, 392, and 398; CDR2sequences having an amino acid sequence selected from the groupconsisting of SEQ ID NOs: 285, 291, 297, 303, 309, 315, 321, 327, 333,339, 345, 351, 357, 363, 369, 375, 381, 387, 393, and 399; and CDR3sequences consisting of an amino acid sequence selected from the groupconsisting of SEQ ID NOs: 286, 292, 298, 304, 310, 316, 322, 328, 334,340, 346, 352, 358, 364, 370, 376, 382, 388, 394, and 400, respectively.Thus, such antibodies contain the VH and VL CDR sequences of monoclonalantibodies, yet may contain different framework sequences from theseantibodies.

Such framework sequences can be obtained from public DNA databases orpublished references that include germline antibody gene sequences. Forexample, germline DNA sequences for human heavy and light chain variableregion genes can be found in the “VBase” human germline sequencedatabase (available on the world wide web at mrc-cpe.cam.ac.uk/vbase),as well as in Kabat, E. A., et al., 1991 Sequences of Proteins ofImmunological Interest, Fifth Edition, U.S. Department of Health andHuman Services, NIH Publication No. 91-3242; Tomlinson, I. M., et al.,1992 J. Mol. Biol. 227:776-798; and Cox, J. P. L. et al., 1994 Eur. JImmunol. 24:827-836; the contents of each of which are expresslyincorporated herein by reference.

An example of framework sequences for use in the antibodies of theinvention are those that are structurally similar to the frameworksequences used by selected antibodies of the invention, e.g., consensussequences and/or framework sequences used by monoclonal antibodies ofthe invention. The VH CDR1, 2 and 3 sequences, and the VL CDR1, 2 and 3sequences, can be grafted onto framework regions that have the identicalsequence as that found in the germline immunoglobulin gene from whichthe framework sequence derive, or the CDR sequences can be grafted ontoframework regions that contain one or more mutations as compared to thegermline sequences. For example, it has been found that in certaininstances it is beneficial to mutate residues within the frameworkregions to maintain or enhance the antigen binding ability of theantibody (see e.g., U.S. Pat. Nos. 5,530,101; 5,585,089; 5,693,762 and6,180,370 to Queen et al). Frameworks that can be utilized as scaffoldson which to build the antibodies and antigen binding fragments describedherein include, but are not limited to VH1A, VH1B, VH3, Vk1, VI2, andVk2. Additional frameworks are known in the art and may be found, forexample, in the vBase data base on the world wide web atvbase.mrc-cpe.cam.ac.uk/index.php?&MMN_position=1:1.

Accordingly, an embodiment of the invention relates to isolated Factor Pbinding antibodies, or antigen binding fragments thereof, comprising aheavy chain variable region comprising an amino acid sequence selectedfrom the group consisting of SEQ ID NOs: 7, 21, 35, 49, 63, 77, 91, 105,119, 133, 147, 161, 175, 189, 203, 217, 231, 245, 259 and 273, or anamino acid sequence having one, two, three, four or five amino acidsubstitutions, deletions or additions in the framework region of suchsequences, and further comprising a light chain variable region havingan amino acid sequence selected from the group consisting of SEQ ID NOs:8, 22, 36, 50, 64, 78, 92, 106, 120, 134, 148, 162, 176, 190, 204, 218,232, 246, 260, and 274, or an amino acid sequence having one, two,three, four or five amino acid substitutions, deletions or additions inthe framework region of such sequences.

Another type of variable region modification is to mutate amino acidresidues within the VH and/or VL CDR1, CDR2 and/or CDR3 regions tothereby improve one or more binding properties (e.g., affinity) of theantibody of interest, known as “affinity maturation.” Site-directedmutagenesis or PCR-mediated mutagenesis can be performed to introducethe mutation(s) and the effect on antibody binding, or other functionalproperty of interest, can be evaluated in in vitro or in vivo assays asdescribed herein and provided in the Examples. Conservativemodifications (as discussed above) can be introduced. The mutations maybe amino acid substitutions, additions or deletions. Moreover, typicallyno more than one, two, three, four or five residues within a CDR regionare altered.

Accordingly, in another embodiment, the invention provides isolatedFactor P-binding antibodies, or antigen binding fragments thereof,consisting of a heavy chain variable region having a VH CDR1 regionconsisting of an amino acid sequence selected from the group having SEQID NOs: 1, 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155, 169, 183,197, 211, 225, 239, 253, and 267 or an amino acid sequence having one,two, three, four or five amino acid substitutions, deletions oradditions as compared to SEQ ID NOs: 1, 15, 29, 43, 57, 71, 85, 99, 113,127, 141, 155, 169, 183, 197, 211, 225, 239, 253, or 267; a VH CDR2region having an amino acid sequence selected from the group consistingof SEQ ID NOs: 2, 16, 30, 44, 58, 72, 86, 100, 114, 128, 142, 156, 170,184, 198, 212, 226, 240, 254, and 268 or an amino acid sequence havingone, two, three, four or five amino acid substitutions, deletions oradditions as compared to SEQ ID NOs: 2, 16, 30, 44, 58, 72, 86, 100,114, 128, 142, 156, 170, 184, 198, 212, 226, 240, 254, or 268; a VH CDR3region having an amino acid sequence selected from the group consistingof SEQ ID NOs: 3, 17, 31, 45, 59, 73, 87, 101, 115, 129, 143, 157, 171,185, 199, 213, 227, 241, 255, and 269, or an amino acid sequence havingone, two, three, four or five amino acid substitutions, deletions oradditions as compared to SEQ ID NOs: 3, 17, 31, 45, 59, 73, 87, 101,115, 129, 143, 157, 171, 185, 199, 213, 227, 241, 255, or 269; a VL CDR1region having an amino acid sequence selected from the group consistingof SEQ ID NOs: 4, 18, 32, 46, 60, 74, 88, 102, 116, 130, 144, 158, 172,186, 200, 214, 228, 242, 256, and 270, or an amino acid sequence havingone, two, three, four or five amino acid substitutions, deletions oradditions as compared to SEQ ID NOs: 4, 18, 32, 46, 60, 74, 88, 102,116, 130, 144, 158, 172, 186, 200, 214, 228, 242, 256, or 270; a VL CDR2region having an amino acid sequence selected from the group consistingof SEQ ID NOs: 5, 19, 33, 47, 61, 75, 89, 103, 117, 131, 145, 159, 173,187, 201, 215, 229, 243, 257, and 271, or an amino acid sequence havingone, two, three, four or five amino acid substitutions, deletions oradditions as compared to SEQ ID NOs: 5, 19, 33, 47, 61, 75, 89, 103,117, 131, 145, 159, 173, 187, 201, 215, 229, 243, 257, or 271; and a VLCDR3 region having an amino acid sequence selected from the groupconsisting of SEQ ID NOs: 6, 20, 34, 48, 62, 76, 90, 104, 118, 132, 146,160, 174, 188, 202, 216, 230, 244, 258, and 272, or an amino acidsequence having one, two, three, four or five amino acid substitutions,deletions or additions as compared to SEQ ID NOs: 6, 20, 34, 48, 62, 76,90, 104, 118, 132, 146, 160, 174, 188, 202, 216, 230, 244, 258, or 272.

Accordingly, in another embodiment, the invention provides isolatedFactor P-binding antibodies, or antigen binding fragments thereof,consisting of a heavy chain variable region having a VH CDR1 regionconsisting of an amino acid sequence selected from the group having SEQID NOs: 281, 287, 293, 299, 305, 311, 317, 323, 329, 335, 341, 347, 353,359, 365, 371, 377, 383, 389, and 395 or an amino acid sequence havingone, two, three, four or five amino acid substitutions, deletions oradditions as compared to SEQ ID NOs: 281, 287, 293, 299, 305, 311, 317,323, 329, 335, 341, 347, 353, 359, 365, 371, 377, 383, 389, or 395; a VHCDR2 region having an amino acid sequence selected from the groupconsisting of SEQ ID NOs: 282, 288, 294, 300, 306, 312, 318, 324, 330,336, 342, 348, 354, 360, 366, 372, 378, 384, 390, and 396 or an aminoacid sequence having one, two, three, four or five amino acidsubstitutions, deletions or additions as compared to SEQ ID NOs: 282,288, 294, 300, 306, 312, 318, 324, 330, 336, 342, 348, 354, 360, 366,372, 378, 384, 390, or 396; a VH CDR3 region having an amino acidsequence selected from the group consisting of SEQ ID NOs: 283, 289,295, 301, 307, 313, 319, 325, 331, 337, 343, 349, 355, 361, 367, 373,379, 385, 391, and 397, or an amino acid sequence having one, two,three, four or five amino acid substitutions, deletions or additions ascompared to SEQ ID NOs: 283, 289, 295, 301, 307, 313, 319, 325, 331,337, 343, 349, 355, 361, 367, 373, 379, 385, 391, or 397; a VL CDR1region having an amino acid sequence selected from the group consistingof SEQ ID NOs: 284, 290, 296, 302, 308, 314, 320, 326, 332, 338, 344,350, 356, 362, 368, 374, 380, 386, 392, and 398, or an amino acidsequence having one, two, three, four or five amino acid substitutions,deletions or additions as compared to SEQ ID NOs: 284, 290, 296, 302,308, 314, 320, 326, 332, 338, 344, 350, 356, 362, 368, 374, 380, 386,392, or 398; a VL CDR2 region having an amino acid sequence selectedfrom the group consisting of SEQ ID NOs: 285, 291, 297, 303, 309, 315,321, 327, 333, 339, 345, 351, 357, 363, 369, 375, 381, 387, 393, and399, or an amino acid sequence having one, two, three, four or fiveamino acid substitutions, deletions or additions as compared to SEQ IDNOs: 285, 291, 297, 303, 309, 315, 321, 327, 333, 339, 345, 351, 357,363, 369, 375, 381, 387, 393, or 399; and a VL CDR3 region having anamino acid sequence selected from the group consisting of SEQ ID NOs:286, 292, 298, 304, 310, 316, 322, 328, 334, 340, 346, 352, 358, 364,370, 376, 382, 388, 394, and 400, or an amino acid sequence having one,two, three, four or five amino acid substitutions, deletions oradditions as compared to SEQ ID NOs: 286, 292, 298, 304, 310, 316, 322,328, 334, 340, 346, 352, 358, 364, 370, 376, 382, 388, 394, or 400.

Grafting Antigen-Binding Domains into Alternative Frameworks orScaffolds

A wide variety of antibody/immunoglobulin frameworks or scaffolds can beemployed so long as the resulting polypeptide includes at least onebinding region which specifically binds to Factor P. Such frameworks orscaffolds include the 5 main idiotypes of human immunoglobulins, orfragments thereof, and include immunoglobulins of other animal species,preferably having humanized aspects. Single heavy-chain antibodies suchas those identified in camelids are of particular interest in thisregard. Novel frameworks, scaffolds and fragments continue to bediscovered and developed by those skilled in the art.

In one aspect, the invention pertains to generating non-immunoglobulinbased antibodies using non-immunoglobulin scaffolds onto which CDRs ofthe invention can be grafted. Known or future non-immunoglobulinframeworks and scaffolds may be employed, as long as they comprise abinding region specific for the target Factor P protein. Knownnon-immunoglobulin frameworks or scaffolds include, but are not limitedto, fibronectin (Compound Therapeutics, Inc., Waltham, Mass.), ankyrin(Molecular Partners AG, Zurich, Switzerland), domain antibodies(Domantis, Ltd., Cambridge, Mass., and Ablynx nv, Zwijnaarde, Belgium),lipocalin (Pieris Proteolab AG, Freising, Germany), small modularimmuno-pharmaceuticals (Trubion Pharmaceuticals Inc., Seattle, Wash.),maxybodies (Avidia, Inc., Mountain View, Calif.), Protein A (AffibodyAG, Sweden), and affilin (gamma-crystallin or ubiquitin) (Scil ProteinsGmbH, Halle, Germany).

The fibronectin scaffolds are based on fibronectin type III domain(e.g., the tenth module of the fibronectin type III (10 Fn3 domain)).The fibronectin type III domain has 7 or 8 beta strands which aredistributed between two beta sheets, which themselves pack against eachother to form the core of the protein, and further containing loops(analogous to CDRs) which connect the beta strands to each other and aresolvent exposed. There are at least three such loops at each edge of thebeta sheet sandwich, where the edge is the boundary of the proteinperpendicular to the direction of the beta strands (see U.S. Pat. No.6,818,418). These fibronectin-based scaffolds are not an immunoglobulin,although the overall fold is closely related to that of the smallestfunctional antibody fragment, the variable region of the heavy chain,which comprises the entire antigen recognition unit in camel and llamaIgG. Because of this structure, the non-immunoglobulin antibody mimicsantigen binding properties that are similar in nature and affinity tothose of antibodies. These scaffolds can be used in a loop randomizationand shuffling strategy in vitro that is similar to the process ofaffinity maturation of antibodies in vivo. These fibronectin-basedmolecules can be used as scaffolds where the loop regions of themolecule can be replaced with CDRs of the invention using standardcloning techniques.

The ankyrin technology is based on using proteins with ankyrin derivedrepeat modules as scaffolds for bearing variable regions which can beused for binding to different targets. The ankyrin repeat module is a 33amino acid polypeptide consisting of two anti-parallel α-helices and aβ-turn. Binding of the variable regions is mostly optimized by usingribosome display.

Avimers are derived from natural A-domain containing protein such asLRP-1. These domains are used by nature for protein-protein interactionsand in human over 250 proteins are structurally based on A-domains.Avimers consist of a number of different “A-domain” monomers (2-10)linked via amino acid linkers. Avimers can be created that can bind tothe target antigen using the methodology described in, for example, U.S.Patent Application Publication Nos. 20040175756; 20050053973;20050048512; and 20060008844.

Affibody affinity ligands are small, simple proteins composed of athree-helix bundle based on the scaffold of one of the IgG-bindingdomains of Protein A. Protein A is a surface protein from the bacteriumStaphylococcus aureus. This scaffold domain consists of 58 amino acids,13 of which are randomized to generate affibody libraries with a largenumber of ligand variants (See e.g., U.S. Pat. No. 5,831,012). Affibodymolecules mimic antibodies, they have a molecular weight of 6 kDa,compared to the molecular weight of antibodies, which is 150 kDa. Inspite of its small size, the binding site of affibody molecules issimilar to that of an antibody.

Anticalins are products developed by the company Pieris ProteoLab AG.They are derived from lipocalins, a widespread group of small and robustproteins that are usually involved in the physiological transport orstorage of chemically sensitive or insoluble compounds. Several naturallipocalins occur in human tissues or body liquids. The proteinarchitecture is reminiscent of immunoglobulins, with hypervariable loopson top of a rigid framework. However, in contrast with antibodies ortheir recombinant fragments, lipocalins are composed of a singlepolypeptide chain with 160 to 180 amino acid residues, being justmarginally bigger than a single immunoglobulin domain. The set of fourloops, which makes up the binding pocket, shows pronounced structuralplasticity and tolerates a variety of side chains. The binding site canthus be reshaped in a proprietary process in order to recognizeprescribed target molecules of different shape with high affinity andspecificity. One protein of lipocalin family, the bilin-binding protein(BBP) of Pieris Brassicae has been used to develop anticalins bymutagenizing the set of four loops. One example of a patent applicationdescribing anticalins is in PCT Publication No. WO 199916873.

Affilin molecules are small non-immunoglobulin proteins which aredesigned for specific affinities towards proteins and small molecules.New affilin molecules can be very quickly selected from two libraries,each of which is based on a different human derived scaffold protein.Affilin molecules do not show any structural homology to immunoglobulinproteins. Currently, two affilin scaffolds are employed, one of which isgamma crystalline, a human structural eye lens protein and the other is“ubiquitin” superfamily proteins. Both human scaffolds are very small,show high temperature stability and are almost resistant to pH changesand denaturing agents. This high stability is mainly due to the expandedbeta sheet structure of the proteins. Examples of gamma crystallinederived proteins are described in W0200104144 and examples of“ubiquitin-like” proteins are described in WO2004106368.

Protein epitope mimetics (PEM) are medium-sized, cyclic, peptide-likemolecules (MW 1-2 kDa) mimicking beta-hairpin secondary structures ofproteins, the major secondary structure involved in protein-proteininteractions.

The present invention provides fully human antibodies that specificallybind to a Factor P protein. Compared to the chimeric or humanizedantibodies, the human Factor P-binding antibodies of the invention havefurther reduced antigenicity when administered to human subjects.

Camelid Antibodies

Antibody proteins obtained from members of the camel and dromedary(Camelus bactrianus and Calelus dromaderius) family including new worldmembers such as llama species (Lama paccos, Lama glama and Lama vicugna)have been characterized with respect to size, structural complexity andantigenicity for human subjects. Certain IgG antibodies from this familyof mammals as found in nature lack light chains, and are thusstructurally distinct from the typical four chain quaternary structurehaving two heavy and two light chains, for antibodies from otheranimals. See PCT/EP93/02214 (WO 94/04678 published 3 Mar. 1994).

A region of the camelid antibody which is the small single variabledomain identified as VHH can be obtained by genetic engineering to yielda small protein having high affinity for a target, resulting in a lowmolecular weight antibody-derived protein known as a “camelid nanobody”.See U.S. Pat. No. 5,759,808 issued Jun. 2, 1998; see also Stijlemans, B.et al., 2004 J Biol Chem 279: 1256-1261; Dumoulin, M. et al., 2003Nature 424: 783-788; Pleschberger, M. et al. 2003 Bioconjugate Chem 14:440-448; Cortez-Retamozo, V. et al. 2002 Int J Cancer 89: 456-62; andLauwereys, M. et al. 1998 EMBO J 17: 3512-3520. Engineered libraries ofcamelid antibodies and antibody fragments are commercially available,for example, from Ablynx, Ghent, Belgium. As with other antibodies ofnon-human origin, an amino acid sequence of a camelid antibody can bealtered recombinantly to obtain a sequence that more closely resembles ahuman sequence, i.e., the nanobody can be “humanized”. Thus the naturallow antigenicity of camelid antibodies to humans can be further reduced.

The camelid nanobody has a molecular weight approximately one-tenth thatof a human IgG molecule, and the protein has a physical diameter of onlya few nanometers. One consequence of the small size is the ability ofcamelid nanobodies to bind to antigenic sites that are functionallyinvisible to larger antibody proteins, i.e., camelid nanobodies areuseful as reagents detect antigens that are otherwise cryptic usingclassical immunological techniques, and as possible therapeutic agents.Thus yet another consequence of small size is that a camelid nanobodycan inhibit as a result of binding to a specific site in a groove ornarrow cleft of a target protein, and hence can serve in a capacity thatmore closely resembles the function of a classical low molecular weightdrug than that of a classical antibody.

The low molecular weight and compact size further result in camelidnanobodies being extremely thermostable, stable to extreme pH and toproteolytic digestion, and poorly antigenic. Another consequence is thatcamelid nanobodies readily move from the circulatory system intotissues, and even cross the blood-brain barrier and can treat disordersthat affect nervous tissue. Nanobodies can further facilitated drugtransport across the blood brain barrier. See U.S. patent application20040161738 published Aug. 19, 2004. These features combined with thelow antigenicity to humans indicate great therapeutic potential.Further, these molecules can be fully expressed in prokaryotic cellssuch as E. coli and are expressed as fusion proteins with bacteriophageand are functional.

Accordingly, a feature of the present invention is a camelid antibody ornanobody having high affinity for Factor P. In certain embodimentsherein, the camelid antibody or nanobody is naturally produced in thecamelid animal, i.e., is produced by the camelid following immunizationwith Factor P or a peptide fragment thereof, using techniques describedherein for other antibodies. Alternatively, the Factor P-binding camelidnanobody is engineered, i.e., produced by selection for example from alibrary of phage displaying appropriately mutagenized camelid nanobodyproteins using panning procedures with Factor P as a target as describedin the examples herein. Engineered nanobodies can further be customizedby genetic engineering to have a half life in a recipient subject offrom 45 minutes to two weeks. In a specific embodiment, the camelidantibody or nanobody is obtained by grafting the CDRs sequences of theheavy or light chain of the human antibodies of the invention intonanobody or single domain antibody framework sequences, as described forexample in PCT/EP93/02214.

Bispecific Molecules and Multivalent Antibodies

In another aspect, the present invention features bispecific ormultispecific molecules comprising a Factor P-binding antibody, or afragment thereof, of the invention. An antibody of the invention, orantigen-binding regions thereof, can be derivatized or linked to anotherfunctional molecule, e.g., another peptide or protein (e.g., anotherantibody or ligand for a receptor) to generate a bispecific moleculethat binds to at least two different binding sites or target molecules.The antibody of the invention may in fact be derivatized or linked tomore than one other functional molecule to generate multi-specificmolecules that bind to more than two different binding sites and/ortarget molecules; such multi-specific molecules are also intended to beencompassed by the term “bispecific molecule” as used herein. To createa bispecific molecule of the invention, an antibody of the invention canbe functionally linked (e.g., by chemical coupling, genetic fusion,noncovalent association or otherwise) to one or more other bindingmolecules, such as another antibody, antibody fragment, peptide orbinding mimetic, such that a bispecific molecule results.

Accordingly, the present invention includes bispecific moleculescomprising at least one first binding specificity for Factor P and asecond binding specificity for a second target epitope. For example, thesecond target epitope is another epitope of Factor P different from thefirst target epitope.

Additionally, for the invention in which the bispecific molecule ismulti-specific, the molecule can further include a third bindingspecificity, in addition to the first and second target epitope.

In one embodiment, the bispecific molecules of the invention comprise asa binding specificity at least one antibody, or an antibody fragmentthereof, including, e.g., a Fab, Fab′, F(ab′)2, Fv, or a single chainFv. The antibody may also be a light chain or heavy chain dimer, or anyminimal fragment thereof such as a Fv or a single chain construct asdescribed in Ladner et al. U.S. Pat. No. 4,946,778.

Diabodies are bivalent, bispecific molecules in which VH and VL domainsare expressed on a single polypeptide chain, connected by a linker thatis too short to allow for pairing between the two domains on the samechain. The VH and VL domains pair with complementary domains of anotherchain, thereby creating two antigen binding sites (see e.g., Holliger etal., 1993 Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak et al., 1994Structure 2:1121-1123). Diabodies can be produced by expressing twopolypeptide chains with either the structure VHA-VLB and VHB-VLA (VH-VLconfiguration), or VLA-VHB and VLB-VHA (VL-VH configuration) within thesame cell. Most of them can be expressed in soluble form in bacteria.Single chain diabodies (scDb) are produced by connecting the twodiabody-forming polypeptide chains with linker of approximately 15 aminoacid residues (see Holliger and Winter, 1997 Cancer Immunol.Immunother., 45(3-4):128-30; Wu et al., 1996 Immunotechnology,2(1):21-36). scDb can be expressed in bacteria in soluble, activemonomeric form (see Holliger and Winter, 1997 Cancer Immunol.Immunother., 45(34): 128-30; Wu et al., 1996 Immunotechnology,2(1):21-36; Pluckthun and Pack, 1997 Immunotechnology, 3(2): 83-105;Ridgway et al., 1996 Protein Eng., 9(7):617-21). A diabody can be fusedto Fc to generate a “di-diabody” (see Lu et al., 2004 J. Biol. Chem.,279(4):2856-65).

Other antibodies which can be employed in the bispecific molecules ofthe invention are murine, chimeric and humanized monoclonal antibodies.

Bispecific molecules can be prepared by conjugating the constituentbinding specificities, using methods known in the art. For example, eachbinding specificity of the bispecific molecule can be generatedseparately and then conjugated to one another. When the bindingspecificities are proteins or peptides, a variety of coupling orcross-linking agents can be used for covalent conjugation. Examples ofcross-linking agents include protein A, carbodiimide,N-succinimidyl-S-acetyl-thioacetate (SATA),5,5′-dithiobis(2-nitrobenzoic acid) (DTNB), o-phenylenedimaleimide(oPDM), N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), andsulfosuccinimidyl 4-(N-maleimidomethyl)cyclohaxane-1-carboxylate(sulfo-SMCC) (see e.g., Karpovsky et al., 1984 J. Exp. Med. 160:1686;Liu, M A et al., 1985 Proc. Natl. Acad. Sci. USA 82:8648). Other methodsinclude those described in Paulus, 1985 Behring Ins. Mitt. No. 78,118-132; Brennan et al., 1985 Science 229:81-83), and Glennie et al.,1987 J. Immunol. 139: 2367-2375). Conjugating agents are SATA andsulfo-SMCC, both available from Pierce Chemical Co. (Rockford, Ill.).

When the binding specificities are antibodies, they can be conjugated bysulfhydryl bonding of the C-terminus hinge regions of the two heavychains. In a particularly embodiment, the hinge region is modified tocontain an odd number of sulfhydryl residues, for example one, prior toconjugation.

Alternatively, both binding specificities can be encoded in the samevector and expressed and assembled in the same host cell. This method isparticularly useful where the bispecific molecule is a mAb x mAb, mAb xFab, Fab x F(ab′)2 or ligand x Fab fusion protein. A bispecific moleculeof the invention can be a single chain molecule comprising one singlechain antibody and a binding determinant, or a single chain bispecificmolecule comprising two binding determinants. Bispecific molecules maycomprise at least two single chain molecules. Methods for preparingbispecific molecules are described for example in U.S. Pat. No.5,260,203; U.S. Pat. No. 5,455,030; U.S. Pat. No. 4,881,175; U.S. Pat.No. 5,132,405; U.S. Pat. No. 5,091,513; U.S. Pat. No. 5,476,786; U.S.Pat. No. 5,013,653; U.S. Pat. No. 5,258,498; and U.S. Pat. No.5,482,858.

Binding of the bispecific molecules to their specific targets can beconfirmed by, for example, enzyme-linked immunosorbent assay (ELISA),radioimmunoassay (REA), FACS analysis, bioassay (e.g., growthinhibition), or Western Blot assay. Each of these assays generallydetects the presence of protein-antibody complexes of particularinterest by employing a labeled reagent (e.g., an antibody) specific forthe complex of interest.

In another aspect, the present invention provides multivalent compoundscomprising at least two identical or different antigen-binding portionsof the antibodies of the invention binding to Factor P. Theantigen-binding portions can be linked together via protein fusion orcovalent or non covalent linkage. Alternatively, methods of linkage havebeen described for the bispecific molecules. Tetravalent compounds canbe obtained for example by cross-linking antibodies of the antibodies ofthe invention with an antibody that binds to the constant regions of theantibodies of the invention, for example the Fc or hinge region.

Trimerizing domain are described for example in Borean patent EP 1 012280B1. Pentamerizing modules are described for example inPCT/EP97/05897.

Antibodies with Extended Half Life

The present invention provides for antibodies that specifically bind toFactor P protein which have an extended half-life in vivo.

Many factors may affect a protein's half life in vivo. For examples,kidney filtration, metabolism in the liver, degradation by proteolyticenzymes (proteases), and immunogenic responses (e.g., proteinneutralization by antibodies and uptake by macrophages and dentriticcells). A variety of strategies can be used to extend the half life ofthe antibodies of the present invention. For example, by chemicallinkage to polyethyleneglycol (PEG), reCODE PEG, antibody scaffold,polysialic acid (PSA), hydroxyethyl starch (HES), albumin-bindingligands, and carbohydrate shields; by genetic fusion to proteins bindingto serum proteins, such as albumin, IgG, FcRn, and transferring; bycoupling (genetically or chemically) to other binding moieties that bindto serum proteins, such as nanoboies, Fabs, DARPins, avimers,affibodies, and anticalins; by genetic fusion to rPEG, albumin, domainof albumin, albumin-binding proteins, and Fc; or by incorporation intonancarriers, slow release formulations, or medical devices.

To prolong the serum circulation of antibodies in vivo, inert polymermolecules such as high molecular weight PEG can be attached to theantibodies or a fragment thereof with or without a multifunctionallinker either through site-specific conjugation of the PEG to the N- orC-terminus of the antibodies or via epsilon-amino groups present onlysine residues. To pegylate an antibody, the antibody, or fragmentthereof, typically is reacted with polyethylene glycol (PEG), such as areactive ester or aldehyde derivative of PEG, under conditions in whichone or more PEG groups become attached to the antibody or antibodyfragment. The pegylation can be carried out by an acylation reaction oran alkylation reaction with a reactive PEG molecule (or an analogousreactive water-soluble polymer). As used herein, the term “polyethyleneglycol” is intended to encompass any of the forms of PEG that have beenused to derivatize other proteins, such as mono (C1-C10) alkoxy- oraryloxy-polyethylene glycol or polyethylene glycol-maleimide. In certainembodiments, the antibody to be pegylated is an aglycosylated antibody.Linear or branched polymer derivatization that results in minimal lossof biological activity will be used. The degree of conjugation can beclosely monitored by SDS-PAGE and mass spectrometry to ensure properconjugation of PEG molecules to the antibodies. Unreacted PEG can beseparated from antibody-PEG conjugates by size-exclusion or byion-exchange chromatography. PEG-derivatized antibodies can be testedfor binding activity as well as for in vivo efficacy using methodswell-known to those of skill in the art, for example, by immunoassaysdescribed herein. Methods for pegylating proteins are known in the artand can be applied to the antibodies of the invention. See for example,EP 0 154 316 by Nishimura et al. and EP 0 401 384 by Ishikawa et al.

Other modified pegylation technologies include reconstituting chemicallyorthogonal directed engineering technology (ReCODE PEG), whichincorporates chemically specified side chains into biosynthetic proteinsvia a reconstituted system that includes tRNA synthetase and tRNA. Thistechnology enables incorporation of more than 30 new amino acids intobiosynthetic proteins in E. coli, yeast, and mammalian cells. The tRNAincorporates a nonnative amino acid any place an amber codon ispositioned, converting the amber from a stop codon to one that signalsincorporation of the chemically specified amino acid.

Recombinant pegylation technology (rPEG) can also be used for serumhalflife extension. This technology involves genetically fusing a300-600 amino acid unstructured protein tail to an existingpharmaceutical protein. Because the apparent molecular weight of such anunstructured protein chain is about 15-fold larger than its actualmolecular weight, the serum halflife of the protein is greatlyincreased. In contrast to traditional PEGylation, which requireschemical conjugation and repurification, the manufacturing process isgreatly simplified and the product is homogeneous.

Polysialytion is another technology, which uses the natural polymerpolysialic acid (PSA) to prolong the active life and improve thestability of therapeutic peptides and proteins. PSA is a polymer ofsialic acid (a sugar). When used for protein and therapeutic peptidedrug delivery, polysialic acid provides a protective microenvironment onconjugation. This increases the active life of the therapeutic proteinin the circulation and prevents it from being recognized by the immunesystem. The PSA polymer is naturally found in the human body. It wasadopted by certain bacteria which evolved over millions of years to coattheir walls with it. These naturally polysialylated bacteria were thenable, by virtue of molecular mimicry, to foil the body's defense system.PSA, nature's ultimate stealth technology, can be easily produced fromsuch bacteria in large quantities and with predetermined physicalcharacteristics. Bacterial PSA is completely non-immunogenic, even whencoupled to proteins, as it is chemically identical to PSA in the humanbody.

Another technology includes the use of hydroxyethyl starch (“HES”)derivatives linked to antibodies. HES is a modified natural polymerderived from waxy maize starch and can be metabolized by the body'senzymes. HES solutions are usually administered to substitute deficientblood volume and to improve the rheological properties of the blood.Hesylation of an antibody enables the prolongation of the circulationhalf-life by increasing the stability of the molecule, as well as byreducing renal clearance, resulting in an increased biological activity.By varying different parameters, such as the molecular weight of HES, awide range of HES antibody conjugates can be customized.

Antibodies having an increased half-life in vivo can also be generatedintroducing one or more amino acid modifications (i.e., substitutions,insertions or deletions) into an IgG constant domain, or FcRn bindingfragment thereof (preferably a Fc or hinge Fc domain fragment). See,e.g., International Publication No. WO 98/23289; InternationalPublication No. WO 97/34631; and U.S. Pat. No. 6,277,375.

Further, antibodies can be conjugated to albumin (e.g., human serumalbumin; HSA) in order to make the antibody or antibody fragment morestable in vivo or have a longer half life in vivo. The techniques arewell-known in the art, see, e.g., International Publication Nos. WO93/15199, WO 93/15200, and WO 01/77137; and European Patent No. EP413,622. In addition, in the context of a bispecific antibody asdescribed above, the specificities of the antibody can be designed suchthat one binding domain of the antibody binds to Factor P while a secondbinding domain of the antibody binds to serum albumin, preferably HSA.

The strategies for increasing half life is especially useful innanobodies, fibronectin-based binders, and other antibodies or proteinsfor which increased in vivo half life is desired.

Antibody Conjugates

The present invention provides antibodies or fragments thereof thatspecifically bind to a Factor P protein recombinantly fused orchemically conjugated (including both covalent and non-covalentconjugations) to a heterologous protein or polypeptide (or fragmentthereof, preferably to a polypeptide of at least 10, at least 20, atleast 30, at least 40, at least 50, at least 60, at least 70, at least80, at least 90 or at least 100 amino acids) to generate fusionproteins. In particular, the invention provides fusion proteinscomprising an antigen-binding fragment of an antibody described herein(e.g., a Fab fragment, Fd fragment, Fv fragment, F(ab)2 fragment, a VHdomain, a VH CDR, a VL domain or a VL CDR) and a heterologous protein,polypeptide, or peptide. Methods for fusing or conjugating proteins,polypeptides, or peptides to an antibody or an antibody fragment areknown in the art. See, e.g., U.S. Pat. Nos. 5,336,603, 5,622,929,5,359,046, 5,349,053, 5,447,851, and 5,112,946; European Patent Nos. EP307,434 and EP 367,166; International Publication Nos. WO 96/04388 andWO 91/06570; Ashkenazi et al., 1991, Proc. Natl. Acad. Sci. USA 88:10535-10539; Zheng et al., 1995, J. Immunol. 154:5590-5600; and Vil etal., 1992, Proc. Natl. Acad. Sci. USA 89:11337-11341.

Additional fusion proteins may be generated through the techniques ofgene-shuffling, motif-shuffling, exon-shuffling, and/or codon-shuffling(collectively referred to as “DNA shuffling”). DNA shuffling may beemployed to alter the activities of antibodies of the invention orfragments thereof (e.g., antibodies or fragments thereof with higheraffinities and lower dissociation rates). See, generally, U.S. Pat. Nos.5,605,793, 5,811,238, 5,830,721, 5,834,252, and 5,837,458; Patten etal., 1997, Curr. Opinion Biotechnol. 8:724-33; Harayama, 1998, TrendsBiotechnol. 16(2):76-82; Hansson, et al., 1999, J. Mol. Biol.287:265-76; and Lorenzo and Blasco, 1998, Biotechniques 24(2):308-313(each of these patents and publications are hereby incorporated byreference in its entirety). Antibodies or fragments thereof, or theencoded antibodies or fragments thereof, may be altered by beingsubjected to random mutagenesis by error-prone PCR, random nucleotideinsertion or other methods prior to recombination. A polynucleotideencoding an antibody or fragment thereof that specifically binds to aFactor P protein may be recombined with one or more components, motifs,sections, parts, domains, fragments, etc. of one or more heterologousmolecules.

Moreover, the antibodies or fragments thereof can be fused to markersequences, such as a peptide to facilitate purification. In preferredembodiments, the marker amino acid sequence is a hexa-histidine peptide,such as the tag provided in a pQE vector (QIAGEN, Inc., 9259 EtonAvenue, Chatsworth, Calif., 91311), among others, many of which arecommercially available. As described in Gentz et al., 1989, Proc. Natl.Acad. Sci. USA 86:821-824, for instance, hexa-histidine provides forconvenient purification of the fusion protein. Other peptide tags usefulfor purification include, but are not limited to, the hemagglutinin(“HA”) tag, which corresponds to an epitope derived from the influenzahemagglutinin protein (Wilson et al., 1984, Cell 37:767), and the “flag”tag.

In other embodiments, antibodies of the present invention or fragmentsthereof conjugated to a diagnostic or detectable agent. Such antibodiescan be useful for monitoring or prognosing the onset, development,progression and/or severity of a disease or disorder as part of aclinical testing procedure, such as determining the efficacy of aparticular therapy. Such diagnosis and detection can accomplished bycoupling the antibody to detectable substances including, but notlimited to, various enzymes, such as, but not limited to, horseradishperoxidase, alkaline phosphatase, beta-galactosidase, oracetylcholinesterase; prosthetic groups, such as, but not limited to,streptavidinlbiotin and avidin/biotin; fluorescent materials, such as,but not limited to, umbelliferone, fluorescein, fluoresceinisothiocynate, rhodamine, dichlorotriazinylamine fluorescein, dansylchloride or phycoerythrin; luminescent materials, such as, but notlimited to, luminol; bioluminescent materials, such as but not limitedto, luciferase, luciferin, and aequorin; radioactive materials, such as,but not limited to, iodine (131I, 125I, 123I, and 121I,), carbon (14C),sulfur (35S), tritium (3H), indium (115In, 113In, 112In, and 111In,),technetium (99Tc), thallium (201Ti), gallium (68Ga, 67Ga), palladium(103Pd), molybdenum (99Mo), xenon (133Xe), fluorine (18F), 153Sm, 177Lu,159Gd, 149Pm, 140La, 175Yb, 166Ho, 90Y, 47Sc, 186Re, 188Re, 142 Pr,105Rh, 97Ru, 68Ge, 57Co, 65Zn, 85Sr, 32P, 153Gd, 169Yb, 51Cr, 54Mn,75Se, 113Sn, and 117Tin; and positron emitting metals using variouspositron emission tomographies, and noradioactive paramagnetic metalions.

The present invention further encompasses uses of antibodies orfragments thereof conjugated to a therapeutic moiety. An antibody orfragment thereof may be conjugated to a therapeutic moiety such as acytotoxin, e.g., a cytostatic or cytocidal agent, a therapeutic agent ora radioactive metal ion, e.g., alpha-emitters. A cytotoxin or cytotoxicagent includes any agent that is detrimental to cells.

Further, an antibody or fragment thereof may be conjugated to atherapeutic moiety or drug moiety that modifies a given biologicalresponse. Therapeutic moieties or drug moieties are not to be construedas limited to classical chemical therapeutic agents. For example, thedrug moiety may be a protein, peptide, or polypeptide possessing adesired biological activity. Such proteins may include, for example, atoxin such as abrin, ricin A, pseudomonas exotoxin, cholera toxin, ordiphtheria toxin; a protein such as tumor necrosis factor, α-interferon,β-interferon, nerve growth factor, platelet derived growth factor,tissue plasminogen activator, an apoptotic agent, an anti-angiogenicagent; or, a biological response modifier such as, for example, alymphokine.

Moreover, an antibody can be conjugated to therapeutic moieties such asa radioactive metal ion, such as alph-emiters such as 213Bi ormacrocyclic chelators useful for conjugating radiometal ions, includingbut not limited to, 131In, 131LU, 131Y, 131Ho, 131Sm, to polypeptides.In certain embodiments, the macrocyclic chelator is1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (DOTA) whichcan be attached to the antibody via a linker molecule. Such linkermolecules are commonly known in the art and described in Denardo et al.,1998, Clin Cancer Res. 4(10):2483-90; Peterson et al., 1999, Bioconjug.Chem. 10(4):553-7; and Zimmerman et al., 1999, Nucl. Med. Biol.26(8):943-50, each incorporated by reference in their entireties.

Techniques for conjugating therapeutic moieties to antibodies are wellknown, see, e.g., Arnon et al., “Monoclonal Antibodies ForImmunotargeting Of Drugs In Cancer Therapy”, in Monoclonal AntibodiesAnd Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss,Inc. 1985); Hellstrom et al., “Antibodies For Drug Delivery”, inControlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53(Marcel Dekker, Inc. 1987); Thorpe, “Antibody Carriers Of CytotoxicAgents In Cancer Therapy: A Review”, in Monoclonal Antibodies 84:Biological And Clinical Applications, Pinchera et al. (eds.), pp.475-506 (1985); “Analysis, Results, And Future Prospective Of TheTherapeutic Use Of Radiolabeled Antibody In Cancer Therapy”, inMonoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al.(eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al., 1982,Immunol. Rev. 62:119-58.

Antibodies may also be attached to solid supports, which areparticularly useful for immunoassays or purification of the targetantigen. Such solid supports include, but are not limited to, glass,cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride orpolypropylene.

Methods of Producing Antibodies of the Invention

Nucleic Acids Encoding the Antibodies

The invention provides substantially purified nucleic acid moleculeswhich encode polypeptides comprising segments or domains of the FactorP-binding antibody chains described above. Some of the nucleic acids ofthe invention comprise the nucleotide sequence encoding the heavy chainvariable region shown in SEQ ID NO: 7, 21, 35, 49, 63, 77, 91, 105, 119,133, 147, 161, 175, 189, 203, 217, 231, 245, 259 or 273, and/or thenucleotide sequence encoding the light chain variable region shown inSEQ ID NO: 8, 22, 36, 50, 64, 78, 92, 106, 120, 134, 148, 162, 176, 190,204, 218, 232, 246, 260, or 274. In a specific embodiment, the nucleicacid molecules are those identified in Table 1. Some other nucleic acidmolecules of the invention comprise nucleotide sequences that aresubstantially identical (e.g., at least 65, 80%, 95%, or 99%) to thenucleotide sequences of those identified in Table 1. When expressed fromappropriate expression vectors, polypeptides encoded by thesepolynucleotides are capable of exhibiting Factor P antigen bindingcapacity.

Also provided in the invention are polynucleotides which encode at leastone CDR region and usually all three CDR regions from the heavy or lightchain of the Factor P-binding antibody set forth above. Some otherpolynucleotides encode all or substantially all of the variable regionsequence of the heavy chain and/or the light chain of the FactorP-binding antibody set forth above. Because of the degeneracy of thecode, a variety of nucleic acid sequences will encode each of theimmunoglobulin amino acid sequences.

The nucleic acid molecules of the invention can encode both a variableregion and a constant region of the antibody. Some of nucleic acidsequences of the invention comprise nucleotides encoding a mature heavychain sequence that is substantially identical (e.g., at least 80%, 90%,or 99%) to the mature heavy chain sequence set forth in SEQ ID NO: 9,23, 37, 51, 65, 79, 93, 107, 121, 135, 149, 163, 177, 191, 205, 219,233, 247, 261 or 275. Some other nucleic acid sequences comprisingnucleotide encoding a mature light chain sequence that is substantiallyidentical (e.g., at least 80%, 90%, or 99%) to the mature light chainsequence set forth in SEQ ID NO: 10, 24, 38, 52, 66, 80, 94, 108, 122,136, 150, 164, 178, 192, 206, 220, 234, 248, 262, or 276.

The polynucleotide sequences can be produced by de novo solid-phase DNAsynthesis or by PCR mutagenesis of an existing sequence (e.g., sequencesas described in the Examples below) encoding a Factor P-binding antibodyor its binding fragment. Direct chemical synthesis of nucleic acids canbe accomplished by methods known in the art, such as the phosphotriestermethod of Narang et al., 1979, Meth. Enzymol. 68:90; the phosphodiestermethod of Brown et al., Meth. Enzymol. 68:109, 1979; thediethylphosphoramidite method of Beaucage et al., Tetra. Lett., 22:1859,1981; and the solid support method of U.S. Pat. No. 4,458,066.Introducing mutations to a polynucleotide sequence by PCR can beperformed as described in, e.g., PCR Technology: Principles andApplications for DNA Amplification, H. A. Erlich (Ed.), Freeman Press,NY, NY, 1992; PCR Protocols: A Guide to Methods and Applications, Inniset al. (Ed.), Academic Press, San Diego, Calif., 1990; Mattila et al.,Nucleic Acids Res. 19:967, 1991; and Eckert et al., PCR Methods andApplications 1:17, 1991.

Also provided in the invention are expression vectors and host cells forproducing the Factor P-binding antibodies described above. Variousexpression vectors can be employed to express the polynucleotidesencoding the Factor P-binding antibody chains or binding fragments. Bothviral-based and nonviral expression vectors can be used to produce theantibodies in a mammalian host cell. Nonviral vectors and systemsinclude plasmids, episomal vectors, typically with an expressioncassette for expressing a protein or RNA, and human artificialchromosomes (see, e.g., Harrington et al., Nat Genet 15:345, 1997). Forexample, nonviral vectors useful for expression of the Factor P-bindingpolynucleotides and polypeptides in mammalian (e.g., human) cellsinclude pThioHis A, B & C, pcDNA3.1/His, pEBVHis A, B & C, (Invitrogen,San Diego, Calif.), MPSV vectors, and numerous other vectors known inthe art for expressing other proteins. Useful viral vectors includevectors based on retroviruses, adenoviruses, adenoassociated viruses,herpes viruses, vectors based on SV40, papilloma virus, HBP Epstein Barrvirus, vaccinia virus vectors and Semliki Forest virus (SFV). See, Brentet al., supra; Smith, Annu. Rev. Microbiol. 49:807, 1995; and Rosenfeldet al., Cell 68:143, 1992.

The choice of expression vector depends on the intended host cells inwhich the vector is to be expressed. Typically, the expression vectorscontain a promoter and other regulatory sequences (e.g., enhancers) thatare operably linked to the polynucleotides encoding a Factor P-bindingantibody chain or fragment. In some embodiments, an inducible promoteris employed to prevent expression of inserted sequences except underinducing conditions. Inducible promoters include, e.g., arabinose, lacZ,metallothionein promoter or a heat shock promoter. Cultures oftransformed organisms can be expanded under noninducing conditionswithout biasing the population for coding sequences whose expressionproducts are better tolerated by the host cells. In addition topromoters, other regulatory elements may also be required or desired forefficient expression of a Factor P-binding antibody chain or fragment.These elements typically include an ATG initiation codon and adjacentribosome binding site or other sequences. In addition, the efficiency ofexpression may be enhanced by the inclusion of enhancers appropriate tothe cell system in use (see, e.g., Scharf et al., Results Probl. CellDiffer. 20:125, 1994; and Bittner et al., Meth. Enzymol., 153:516,1987). For example, the SV40 enhancer or CMV enhancer may be used toincrease expression in mammalian host cells.

The expression vectors may also provide a secretion signal sequenceposition to form a fusion protein with polypeptides encoded by insertedFactor P-binding antibody sequences. More often, the inserted FactorP-binding antibody sequences are linked to a signal sequences beforeinclusion in the vector. Vectors to be used to receive sequencesencoding Factor P-binding antibody light and heavy chain variabledomains sometimes also encode constant regions or parts thereof. Suchvectors allow expression of the variable regions as fusion proteins withthe constant regions thereby leading to production of intact antibodiesor fragments thereof. Typically, such constant regions are human.

The host cells for harboring and expressing the Factor P-bindingantibody chains can be either prokaryotic or eukaryotic. E. coli is oneprokaryotic host useful for cloning and expressing the polynucleotidesof the present invention. Other microbial hosts suitable for use includebacilli, such as Bacillus subtilis, and other enterobacteriaceae, suchas Salmonella, Serratia, and various Pseudomonas species. In theseprokaryotic hosts, one can also make expression vectors, which typicallycontain expression control sequences compatible with the host cell(e.g., an origin of replication). In addition, any number of a varietyof well-known promoters will be present, such as the lactose promotersystem, a tryptophan (trp) promoter system, a beta-lactamase promotersystem, or a promoter system from phage lambda. The promoters typicallycontrol expression, optionally with an operator sequence, and haveribosome binding site sequences and the like, for initiating andcompleting transcription and translation. Other microbes, such as yeast,can also be employed to express Factor P-binding polypeptides of theinvention. Insect cells in combination with baculovirus vectors can alsobe used.

In some preferred embodiments, mammalian host cells are used to expressand produce the Factor P-binding polypeptides of the present invention.For example, they can be either a hybridoma cell line expressingendogenous immunoglobulin genes (e.g., the 1D6.C9 myeloma hybridomaclone as described in the Examples) or a mammalian cell line harboringan exogenous expression vector (e.g., the SP2/0 myeloma cellsexemplified below). These include any normal mortal or normal orabnormal immortal animal or human cell. For example, a number ofsuitable host cell lines capable of secreting intact immunoglobulinshave been developed including the CHO cell lines, various Cos celllines, HeLa cells, myeloma cell lines, transformed B-cells andhybridomas. The use of mammalian tissue cell culture to expresspolypeptides is discussed generally in, e.g., Winnacker, FROM GENES TOCLONES, VCH Publishers, N.Y., N.Y., 1987. Expression vectors formammalian host cells can include expression control sequences, such asan origin of replication, a promoter, and an enhancer (see, e.g., Queen,et al., Immunol. Rev. 89:49-68, 1986), and necessary processinginformation sites, such as ribosome binding sites, RNA splice sites,polyadenylation sites, and transcriptional terminator sequences. Theseexpression vectors usually contain promoters derived from mammaliangenes or from mammalian viruses. Suitable promoters may be constitutive,cell type-specific, stage-specific, and/or modulatable or regulatable.Useful promoters include, but are not limited to, the metallothioneinpromoter, the constitutive adenovirus major late promoter, thedexamethasone-inducible MMTV promoter, the SV40 promoter, the MRP polIIIpromoter, the constitutive MPSV promoter, the tetracycline-inducible CMVpromoter (such as the human immediate-early CMV promoter), theconstitutive CMV promoter, and promoter-enhancer combinations known inthe art.

Methods for introducing expression vectors containing the polynucleotidesequences of interest vary depending on the type of cellular host. Forexample, calcium chloride transfection is commonly utilized forprokaryotic cells, whereas calcium phosphate treatment orelectroporation may be used for other cellular hosts. (See generallySambrook, et al., supra). Other methods include, e.g., electroporation,calcium phosphate treatment, liposome-mediated transformation, injectionand microinjection, ballistic methods, virosomes, immunoliposomes,polycation:nucleic acid conjugates, naked DNA, artificial virions,fusion to the herpes virus structural protein VP22 (Elliot and O'Hare,Cell 88:223, 1997), agent-enhanced uptake of DNA, and ex vivotransduction. For long-term, high-yield production of recombinantproteins, stable expression will often be desired. For example, celllines which stably express Factor P-binding antibody chains or bindingfragments can be prepared using expression vectors of the inventionwhich contain viral origins of replication or endogenous expressionelements and a selectable marker gene. Following the introduction of thevector, cells may be allowed to grow for 1-2 days in an enriched mediabefore they are switched to selective media. The purpose of theselectable marker is to confer resistance to selection, and its presenceallows growth of cells which successfully express the introducedsequences in selective media. Resistant, stably transfected cells can beproliferated using tissue culture techniques appropriate to the celltype.

Generation of Monoclonal Antibodies of the Invention

Monoclonal antibodies (mAbs) can be produced by a variety of techniques,including conventional monoclonal antibody methodology e.g., thestandard somatic cell hybridization technique of Kohler and Milstein,1975 Nature 256: 495. Many techniques for producing monoclonal antibodycan be employed e.g., viral or oncogenic transformation of Blymphocytes.

An animal systems for preparing hybridomas include the murine, rat andrabbit systems. Hybridoma production in the mouse is a well establishedprocedure. Immunization protocols and techniques for isolation ofimmunized splenocytes for fusion are known in the art. Fusion partners(e.g., murine myeloma cells) and fusion procedures are also known.

Chimeric or humanized antibodies of the present invention can beprepared based on the sequence of a murine monoclonal antibody preparedas described above. DNA encoding the heavy and light chainimmunoglobulins can be obtained from the murine hybridoma of interestand engineered to contain non-murine (e.g., human) immunoglobulinsequences using standard molecular biology techniques. For example, tocreate a chimeric antibody, the murine variable regions can be linked tohuman constant regions using methods known in the art (see e.g., U.S.Pat. No. 4,816,567 to Cabilly et al.). To create a humanized antibody,the murine CDR regions can be inserted into a human framework usingmethods known in the art. See e.g., U.S. Pat. No. 5,225,539 to Winter,and U.S. Pat. Nos. 5,530,101; 5,585,089; 5693762 and 6180370 to Queen etal.

In a certain embodiment, the antibodies of the invention are humanmonoclonal antibodies. Such human monoclonal antibodies directed againstFactor P can be generated using transgenic or transchromosomic micecarrying parts of the human immune system rather than the mouse system.These transgenic and transchromosomic mice include mice referred toherein as HuMAb mice and KM mice, respectively, and are collectivelyreferred to herein as “human Ig mice.”

The HuMAb mouse (Medarex, Inc.) contains human immunoglobulin geneminiloci that encode un-rearranged human heavy (μ and γ) and κ lightchain immunoglobulin sequences, together with targeted mutations thatinactivate the endogenous μ and κ chain loci (see e.g., Lonberg, et al.,1994 Nature 368(6474): 856-859). Accordingly, the mice exhibit reducedexpression of mouse IgM or κ, and in response to immunization, theintroduced human heavy and light chain transgenes undergo classswitching and somatic mutation to generate high affinity human IgGκmonoclonal (Lonberg, N. et al., 1994 supra; reviewed in Lonberg, N.,1994 Handbook of Experimental Pharmacology 113:49-101; Lonberg, N. andHuszar, D., 1995 Intern. Rev. Immunol. 13: 65-93, and Harding, F. andLonberg, N., 1995 Ann. N. Y. Acad. Sci. 764:536-546). The preparationand use of HuMAb mice, and the genomic modifications carried by suchmice, is further described in Taylor, L. et al., 1992 Nucleic AcidsResearch 20:6287-6295; Chen, J. et at., 1993 International Immunology 5:647-656; Tuaillon et al., 1993 Proc. Natl. Acad. Sci. USA 94:3720-3724;Choi et al., 1993 Nature Genetics 4:117-123; Chen, J. et al., 1993 EMBOJ. 12: 821-830; Tuaillon et al., 1994 J. Immunol. 152:2912-2920; Taylor,L. et al., 1994 International Immunology 579-591; and Fishwild, D. etal., 1996 Nature Biotechnology 14: 845-851, the contents of all of whichare hereby specifically incorporated by reference in their entirety. Seefurther, U.S. Pat. Nos. 5,545,806; 5,569,825; 5,625,126; 5,633,425;5,789,650; 5,877,397; 5,661,016; 5,814,318; 5,874,299; and 5,770,429;all to Lonberg and Kay; U.S. Pat. No. 5,545,807 to Surani et al.; PCTPublication Nos. WO 92103918, WO 93/12227, WO 94/25585, WO 97113852, WO98/24884 and WO 99/45962, all to Lonberg and Kay; and PCT PublicationNo. WO 01/14424 to Korman et al.

In another embodiment, human antibodies of the invention can be raisedusing a mouse that carries human immunoglobulin sequences on transgenesand transchomosomes such as a mouse that carries a human heavy chaintransgene and a human light chain transchromosome. Such mice, referredto herein as “KM mice”, are described in detail in PCT Publication WO02/43478 to Ishida et al.

Still further, alternative transgenic animal systems expressing humanimmunoglobulin genes are available in the art and can be used to raiseFactor P-binding antibodies of the invention. For example, analternative transgenic system referred to as the Xenomouse (Abgenix,Inc.) can be used. Such mice are described in, e.g., U.S. Pat. Nos.5,939,598; 6,075,181; 6,114,598; 6, 150,584 and 6,162,963 toKucherlapati et al.

Moreover, alternative transchromosomic animal systems expressing humanimmunoglobulin genes are available in the art and can be used to raiseFactor P-binding antibodies of the invention. For example, mice carryingboth a human heavy chain transchromosome and a human light chaintranchromosome, referred to as “TC mice” can be used; such mice aredescribed in Tomizuka et al., 2000 Proc. Natl. Acad. Sci. USA97:722-727. Furthermore, cows carrying human heavy and light chaintranschromosomes have been described in the art (Kuroiwa et al., 2002Nature Biotechnology 20:889-894) and can be used to raise FactorP-binding antibodies of the invention.

Human monoclonal antibodies of the invention can also be prepared usingphage display methods for screening libraries of human immunoglobulingenes. Such phage display methods for isolating human antibodies areestablished in the art or described in the examples below. See forexample: U.S. Pat. Nos. 5,223,409; 5,403,484; and 5,571,698 to Ladner etal.; U.S. Pat. Nos. 5,427,908 and 5,580,717 to Dower et al.; U.S. Pat.Nos. 5,969,108 and 6,172,197 to McCafferty et al.; and U.S. Pat. Nos.5,885,793; 6,521,404; 6,544,731; 6,555,313; 6,582,915 and 6,593,081 toGriffiths et al.

Human monoclonal antibodies of the invention can also be prepared usingSCID mice into which human immune cells have been reconstituted suchthat a human antibody response can be generated upon immunization. Suchmice are described in, for example, U.S. Pat. Nos. 5,476,996 and5,698,767 to Wilson et al.

Framework or Fc Engineering

Engineered antibodies of the invention include those in whichmodifications have been made to framework residues within VH and/or VL,e.g. to improve the properties of the antibody. Typically such frameworkmodifications are made to decrease the immunogenicity of the antibody.For example, one approach is to “backmutate” one or more frameworkresidues to the corresponding germline sequence. More specifically, anantibody that has undergone somatic mutation may contain frameworkresidues that differ from the germline sequence from which the antibodyis derived. Such residues can be identified by comparing the antibodyframework sequences to the germline sequences from which the antibody isderived. To return the framework region sequences to their germlineconfiguration, the somatic mutations can be “backmutated” to thegermline sequence by, for example, site-directed mutagenesis. Such“backmutated” antibodies are also intended to be encompassed by theinvention.

Another type of framework modification involves mutating one or moreresidues within the framework region, or even within one or more CDRregions, to remove T cell-epitopes to thereby reduce the potentialimmunogenicity of the antibody. This approach is also referred to as“deimmunization” and is described in further detail in U.S. PatentPublication No. 20030153043 by Carr et al.

In addition or alternative to modifications made within the framework orCDR regions, antibodies of the invention may be engineered to includemodifications within the Fc region, typically to alter one or morefunctional properties of the antibody, such as serum half-life,complement fixation, Fc receptor binding, and/or antigen-dependentcellular cytotoxicity. Furthermore, an antibody of the invention may bechemically modified (e.g., one or more chemical moieties can be attachedto the antibody) or be modified to alter its glycosylation, again toalter one or more functional properties of the antibody. Each of theseembodiments is described in further detail below. The numbering ofresidues in the Fc region is that of the EU index of Kabat.

In one embodiment, the hinge region of CH1 is modified such that thenumber of cysteine residues in the hinge region is altered, e.g.,increased or decreased. This approach is described further in U.S. Pat.No. 5,677,425 by Bodmer et al. The number of cysteine residues in thehinge region of CH1 is altered to, for example, facilitate assembly ofthe light and heavy chains or to increase or decrease the stability ofthe antibody.

In another embodiment, the Fc hinge region of an antibody is mutated todecrease the biological half-life of the antibody. More specifically,one or more amino acid mutations are introduced into the CH2-CH3 domaininterface region of the Fc-hinge fragment such that the antibody hasimpaired Staphylococcyl protein A (SpA) binding relative to nativeFc-hinge domain SpA binding. This approach is described in furtherdetail in U.S. Pat. No. 6,165,745 by Ward et al.

In another embodiment, the antibody is modified to increase itsbiological half-life. Various approaches are possible. For example, oneor more of the following mutations can be introduced: T252L, T254S,T256F, as described in U.S. Pat. No. 6,277,375 to Ward. Alternatively,to increase the biological half life, the antibody can be altered withinthe CH1 or CL region to contain a salvage receptor binding epitope takenfrom two loops of a CH2 domain of an Fc region of an IgG, as describedin U.S. Pat. Nos. 5,869,046 and 6,121,022 by Presta et al.

In yet other embodiments, the Fc region is altered by replacing at leastone amino acid residue with a different amino acid residue to alter theeffector functions of the antibody. For example, one or more amino acidscan be replaced with a different amino acid residue such that theantibody has an altered affinity for an effector ligand but retains theantigen-binding ability of the parent antibody. The effector ligand towhich affinity is altered can be, for example, an Fc receptor or the C1component of complement. This approach is described in further detail inU.S. Pat. Nos. 5,624,821 and 5,648,260, both by Winter et al.

In another embodiment, one or more amino acids selected from amino acidresidues can be replaced with a different amino acid residue such thatthe antibody has altered C1q binding and/or reduced or abolishedcomplement dependent cytotoxicity (CDC). This approach is described infurther detail in U.S. Pat. No. 6,194,551 by Idusogie et al.

In another embodiment, one or more amino acid residues are altered tothereby alter the ability of the antibody to fix complement. Thisapproach is described further in PCT Publication WO 94/29351 by Bodmeret al.

In yet another embodiment, the Fc region is modified to increase theability of the antibody to mediate antibody dependent cellularcytotoxicity (ADCC) and/or to increase the affinity of the antibody foran Fcγ receptor by modifying one or more amino acids. This approach isdescribed further in PCT Publication WO 00/42072 by Presta. Moreover,the binding sites on human IgG1 for FcγRI, FcγRII, FcγRIII and FcRn havebeen mapped and variants with improved binding have been described (seeShields, R. L. et al., 2001 J. Biol. Chen. 276:6591-6604).

In still another embodiment, the glycosylation of an antibody ismodified. For example, an aglycoslated antibody can be made (i.e., theantibody lacks glycosylation). Glycosylation can be altered to, forexample, increase the affinity of the antibody for “antigen’. Suchcarbohydrate modifications can be accomplished by, for example, alteringone or more sites of glycosylation within the antibody sequence. Forexample, one or more amino acid substitutions can be made that result inelimination of one or more variable region framework glycosylation sitesto thereby eliminate glycosylation at that site. Such aglycosylation mayincrease the affinity of the antibody for antigen. Such an approach isdescribed in further detail in U.S. Pat. Nos. 5,714,350 and 6,350,861 byCo et al.

Additionally or alternatively, an antibody can be made that has analtered type of glycosylation, such as a hypofucosylated antibody havingreduced amounts of fucosyl residues or an antibody having increasedbisecting GlcNac structures. Such altered glycosylation patterns havebeen demonstrated to increase the ADCC ability of antibodies. Suchcarbohydrate modifications can be accomplished by, for example,expressing the antibody in a host cell with altered glycosylationmachinery. Cells with altered glycosylation machinery have beendescribed in the art and can be used as host cells in which to expressrecombinant antibodies of the invention to thereby produce an antibodywith altered glycosylation. For example, EP 1,176,195 by Hang et al.describes a cell line with a functionally disrupted FUT8 gene, whichencodes a fucosyl transferase, such that antibodies expressed in such acell line exhibit hypofucosylation. PCT Publication WO 03/035835 byPresta describes a variant CHO cell line, Lecl3 cells, with reducedability to attach fucose to Asn(297)-linked carbohydrates, alsoresulting in hypofucosylation of antibodies expressed in that host cell(see also Shields, R. L. et al., 2002 J. Biol. Chem. 277:26733-26740).PCT Publication WO 99/54342 by Umana et al. describes cell linesengineered to express glycoprotein-modifying glycosyl transferases(e.g., beta(1,4)-N acetylglucosaminyltransferase III (GnTIII)) such thatantibodies expressed in the engineered cell lines exhibit increasedbisecting GlcNac structures which results in increased ADCC activity ofthe antibodies (see also Umana et al., 1999 Nat. Biotech. 17:176-180).

Methods of Engineering Altered Antibodies

As discussed above, the Factor P-binding antibodies having VH and VLsequences or full length heavy and light chain sequences shown hereincan be used to create new Factor P-binding antibodies by modifying fulllength heavy chain and/or light chain sequences, VH and/or VL sequences,or the constant region(s) attached thereto. Thus, in another aspect ofthe invention, the structural features of a Factor P-binding antibody ofthe invention are used to create structurally related Factor P-bindingantibodies that retain at least one functional property of theantibodies of the invention, such as binding to human Factor P and alsoinhibiting one or more functional properties of Factor P (e.g.,inhibiting MAC deposition in a MAC deposition assay, inhibit red bloodcell lysis in a hemolytic assay).

For example, one or more CDR regions of the antibodies of the presentinvention, or mutations thereof, can be combined recombinantly withknown framework regions and/or other CDRs to create additional,recombinantly-engineered, Factor P-binding antibodies of the invention,as discussed above. Other types of modifications include those describedin the previous section. The starting material for the engineeringmethod is one or more of the VH and/or VL sequences provided herein, orone or more CDR regions thereof. To create the engineered antibody, itis not necessary to actually prepare (i.e., express as a protein) anantibody having one or more of the VH and/or VL sequences providedherein, or one or more CDR regions thereof. Rather, the informationcontained in the sequence(s) is used as the starting material to createa “second generation” sequence(s) derived from the original sequence(s)and then the “second generation” sequence(s) is prepared and expressedas a protein.

Accordingly, in another embodiment, the invention provides a method forpreparing a Factor P-binding antibody consisting of a heavy chainvariable region antibody sequence having a CDR1 sequence selected fromthe group consisting of SEQ ID NOs: 1, 15, 29, 43, 57, 71, 85, 99, 113,127, 141, 155, 169, 183, 197, 211, 225, 239, 253, and 267, a CDR2sequence selected from the group consisting of SEQ ID NOs: 2, 16, 30,44, 58, 72, 86, 100, 114, 128, 142, 156, 170, 184, 198, 212, 226, 240,254, and 268, and/or a CDR3 sequence selected from the group consistingof SEQ ID NOs: 3, 17, 31, 45, 59, 73, 87, 101, 115, 129, 143, 157, 171,185, 199, 213, 227, 241, 255, and 269; and a light chain variable regionantibody sequence having a CDR1 sequence selected from the groupconsisting of SEQ ID NOs: 4, 18, 32, 46, 60, 74, 88, 102, 116, 130, 144,158, 172, 186, 200, 214, 228, 242, 256, and 270, a CDR2 sequenceselected from the group consisting of SEQ ID NOs: 5, 19, 33, 47, 61, 75,89, 103, 117, 131, 145, 159, 173, 187, 201, 215, 229, 243, 257, and 271,and/or a CDR3 sequence selected from the group consisting of SEQ ID NOs:6, 20, 34, 48, 62, 76, 90, 104, 118, 132, 146, 160, 174, 188, 202, 216,230, 244, 258, and 272; altering at least one amino acid residue withinthe heavy chain variable region antibody sequence and/or the light chainvariable region antibody sequence to create at least one alteredantibody sequence; and expressing the altered antibody sequence as aprotein.

Accordingly, in another embodiment, the invention provides a method forpreparing a Factor P-binding antibody consisting of a heavy chainvariable region antibody sequence having a CDR1 sequence selected fromthe group consisting of SEQ ID NOs: 281, 287, 293, 299, 305, 311, 317,323, 329, 335, 341, 347, 353, 359, 365, 371, 377, 383, 389, and 395, aCDR2 sequence selected from the group consisting of SEQ ID NOs: 282,288, 294, 300, 306, 312, 318, 324, 330, 336, 342, 348, 354, 360, 366,372, 378, 384, 390, and 396, and/or a CDR3 sequence selected from thegroup consisting of SEQ ID NOs: 283, 289, 295, 301, 307, 313, 319, 325,331, 337, 343, 349, 355, 361, 367, 373, 379, 385, 391, and 397; and alight chain variable region antibody sequence having a CDR1 sequenceselected from the group consisting of SEQ ID NOs: 284, 290, 296, 302,308, 314, 320, 326, 332, 338, 344, 350, 356, 362, 368, 374, 380, 386,392, and 398, a CDR2 sequence selected from the group consisting of SEQID NOs: 285, 291, 297, 303, 309, 315, 321, 327, 333, 339, 345, 351, 357,363, 369, 375, 381, 387, 393, and 399, and/or a CDR3 sequence selectedfrom the group consisting of SEQ ID NOs: 286, 292, 298, 304, 310, 316,322, 328, 334, 340, 346, 352, 358, 364, 370, 376, 382, 388, 394, and400; altering at least one amino acid residue within the heavy chainvariable region antibody sequence and/or the light chain variable regionantibody sequence to create at least one altered antibody sequence; andexpressing the altered antibody sequence as a protein.

Accordingly, in another embodiment, the invention provides a method forpreparing a Factor P-binding antibody optimized for expression in amammalian cell consisting of: a full length heavy chain antibodysequence having a sequence selected from the group of SEQ ID NOs: 9, 23,37, 51, 65, 79, 93, 107, 121, 135, 149, 163, 177, 191, 205, 219, 233,247, 261 and 275; and a full length light chain antibody sequence havinga sequence selected from the group of SEQ ID NOs: 10, 24, 38, 52, 66,80, 94, 108, 122, 136, 150, 164, 178, 192, 206, 220, 234, 248, 262, and276; altering at least one amino acid residue within the full lengthheavy chain antibody sequence and/or the full length light chainantibody sequence to create at least one altered antibody sequence; andexpressing the altered antibody sequence as a protein. In oneembodiment, the alteration of the heavy or light chain is in theframework region of the heavy or light chain.

The altered antibody sequence can also be prepared by screening antibodylibraries having fixed CDR3 sequences or minimal essential bindingdeterminants as described in US20050255552 and diversity on CDR1 andCDR2 sequences. The screening can be performed according to anyscreening technology appropriate for screening antibodies from antibodylibraries, such as phage display technology.

Standard molecular biology techniques can be used to prepare and expressthe altered antibody sequence. The antibody encoded by the alteredantibody sequence(s) is one that retains one, some or all of thefunctional properties of the Factor P-binding antibodies describedherein, which functional properties include, but are not limited to,specifically binding to human and/or cynomolgus Factor P; and theantibody inhibit red blood cell lysis in a hemolytic assay.

In certain embodiments of the methods of engineering antibodies of theinvention, mutations can be introduced randomly or selectively along allor part of an Factor P-binding antibody coding sequence and theresulting modified Factor P-binding antibodies can be screened forbinding activity and/or other functional properties as described herein.Mutational methods have been described in the art. For example, PCTPublication WO 02/092780 by Short describes methods for creating andscreening antibody mutations using saturation mutagenesis, syntheticligation assembly, or a combination thereof. Alternatively, PCTPublication WO 03/074679 by Lazar et al. describes methods of usingcomputational screening methods to optimize physiochemical properties ofantibodies.

In certain embodiments of the invention antibodies have been engineeredto remove sites of deamidation. Deamidation is known to cause structuraland functional changes in a peptide or protein. Deamindation can resultin decreased bioactivity, as well as alterations in pharmacokinetics andantigenicity of the protein pharmaceutical. (Anal Chem. 2005 Mar. 1;77(5):1432-9).

The functional properties of the altered antibodies can be assessedusing standard assays available in the art and/or described herein, suchas those set forth in the Examples (e.g., ELISAs).

Prophylactic and Therapeutic Uses

Antibodies that binds Factor P as described herein, can be used at atherapeutically useful concentration for the treatment of a disease ordisorder associated with increased complement activity by administeringto a subject in need thereof an effective amount of the antibodies orantigen binding fragments of the invention. In a specific embodiment,the present invention provides a method of treating age-related maculardegeneration (AMD) by administering to a subject in need thereof aneffective amount of the antibodies of the invention.

The antibodies of the invention can be used, inter alia, to preventprogression of dry AMD to wet AMD, to slow and/or prevent progression ofgeographic atrophy, to treat or prevent macular edema, to reduce thefrequency of Lucentis injection and to improve vision lost due to dryand wet AMD progression. It can also be used in combination withanti-VEGF therapies for the treatment of wet AMD patients.

Treatment and/or prevention of occular disease such as AMD can bedetermined by an ophthalmologist or health care professional usingclinically relevant measurements of visual function and/or retinalanatomy. Treatment of AMD means any action (e.g., administration of ananti-Factor P antibody described herein) contemplated to improve orpreserve visual function and/or retinal anatomy. In addition, preventionas it relates to AMD means any action (e.g., administration of ananti-Factor P antibody described herein) that prevents or slows aworsening in visual function, retinal anatomy, and/or an AMD diseaseparameter, as defined herein, in a patient at risk for said worsening.

Visual function may include, for example, visual acuity, visual acuitywith low illumination, visual field, central visual field, peripheralvision, contrast sensitivity, dark adaptation, photostress recovery,color discrimination, reading speed, dependence on assistive devices(e.g., large typeface, magnifying devices, telescopes), facialrecognition, proficiency at operating a motor vehicle, ability toperform one or more activities of daily living, and/or patient-reportedsatisfaction related to visual function. THus, treatment of AMD can besaid to occur where a subject has an at least 10% decrease or lack of a10% or more increase in time to a pre-specified degree of darkadaptation. In addition, treatment of AMD can be said to occur where asubject exhibits at least a 10% reduction or lack of a 10% or moreincrease in total area of central visual scotoma expressed as a visualangle determined by a qualified health care professional (i.e.,opthalmologist).

Exemplary measures of visual function include Snellen visual acuity,ETDRS visual acuity, low-luminance visual acuity, Amsler grid, Goldmannvisual field, Humphrey visual field, microperimetry, Pelli-Robsoncharts, SKILL card, Ishihara color plates, Farnsworth D15 or D100 colortest, and validated tests for reading speed, facial recognition, drivingsimulations, and patient reported satisfaction. Thus, treatment of AMDcan be said to be achieved upon a gain of or failure to lose 2 or morelines (or 10 letters) of vision on an ETDRS scale. In addition,treatment of AMD can be said to occur where a subject exhibits at leasta 10% an increase or lack of 10% decrease in reading speed (words perminute). In addition, treatment of AMD can be said to occur where asubject exhibits at least a 20% increase or lack of a 20% decrease inthe proportion of correctly identified plates on an Ishihara test orsequenced disks on a Farnsworth test.

Undesirable aspects of retinal anatomy that may be treated or preventedinclude, for example, drusen, soft drusen, hard drusen, cuticulardrusen, basal laminar drusen, confluent drusen, large drusen (e.g.,greater than 125 microns in diameter), RPE atrophy, photoreceptoratrophy, geographic atrophy, choroidal neovascularization, subretinalneovascularization, retinal neovascularization, classic choroidalneovascularization, occult choroidal neovascularization, retinalangiomatous proliferation, chorioretinal anastomosis, an abnormality ofchoroidal anatomy, subretinal hemorrhage, intraretinal hemorrhage,vitreous hemorrhage, macular scar, subretinal fibrosis, and retinalfibrosis. Thus, treatment of, for example, geographic atrophy can bedetermined by a 20% or more reduction in lesion growth rate as comparedto control or previously documented growth rate in the same subject inthe same eye.

Exemplary means of assessing retinal anatomy include funduscopy, fundusphotography, fluorescein angiography, indocyanine green angiography,ocular coherence tomography (OCT), spectral domain ocular coherencetomography, scanning laser ophthalmoscopy, confocal microscopy, adaptiveoptics, fundus autofluorescence, biopsy, necropsy, andimmunohistochemistry. Thus, AMD can be said to be treated in a subjectupon a 10% reduction in the measurement of macular thickness asdetermined by OCT, and/or a reduction of hyperfluorescence as determinedby fluorescein angiography.

Exemplary measures of retinal anatomy include drusen area, drusenvolume, geographic atrophy lesion area, geographic atrophy growth rate,and neovascular membrane area.

In some embodiments, the present invention provides methods of treatinga complement related disease or disorder by administering to a subjectin need thereof an effective amount of the antibodies of the invention.Examples of known complement related diseases or disorders include:neurological disorders, multiple sclerosis, stroke, Guillain BarreSyndrome, traumatic brain injury, Parkinson's disease, disorders ofinappropriate or undesirable complement activation, hemodialysiscomplications, hyperacute allograft rejection, xenograft rejection,interleukin-2 induced toxicity during IL-2 therapy, inflammatorydisorders, inflammation of autoimmune diseases, Crohn's disease, adultrespiratory distress syndrome, thermal injury including burns orfrostbite, post-ischemic reperfusion conditions, myocardial infarction,balloon angioplasty, post-pump syndrome in cardiopulmonary bypass orrenal bypass, hemodialysis, renal ischemia, mesenteric arteryreperfusion after acrotic reconstruction, infectious disease or sepsis,immune complex disorders and autoimmune diseases, rheumatoid arthritis,systemic lupus erythematosus (SLE), SLE nephritis, proliferativenephritis, hemolytic anemia, and myasthenia gravis. In addition, otherknown complement related disease are lung disease and disorders such asdyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease(COPD), emphysema, pulmonary embolisms and infarcts, pneumonia,fibrogenic dust diseases, inert dusts and minerals (e.g., silicon, coaldust, beryllium, and asbestos), pulmonary fibrosis, organic dustdiseases, chemical injury (due to irritant gasses and chemicals, e.g.,chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide,ammonia, and hydrochloric acid), smoke injury, thermal injury (e.g.,burn, freeze), asthma, allergy, bronchoconstriction, hypersensitivitypneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonaryvasculitis, and immune complex-associated inflammation.

In a specific embodiment, the present invention provides methods oftreating a complement related disease or disorder by administering to asubject in need thereof an effective amount of the antibodies of theinvention, wherein said disease or disorder is asthma, arthritis (e.g.,rheumatoid arthritis), autoimmune heart disease, multiple sclerosis,inflammatory bowel disease, ischemia-reperfusion injuries,Barraquer-Simons Syndrome, hemodialysis, systemic lupus, lupuserythematosus, psoriasis, multiple sclerosis, transplantation, diseasesof the central nervous system such as Alzheimer's disease and otherneurodegenerative conditions, aHUS, glomerulonephritis, bullouspemphigoid or MPGN II.

In a specific embodiment, the present invention provides methods oftreating glomerulonephritis by administering to a subject in needthereof an effective amount of a composition comprising an antibody ofthe present invention. Symptoms of glomerulonephritis include, but notlimited to, proteinuria; reduced glomerular filtration rate (GFR); serumelectrolyte changes including azotemia (uremia, excessive blood ureanitrogen-—BUN) and salt retention, leading to water retention resultingin hypertension and edema; hematuria and abnormal urinary sedimentsincluding red cell casts; hypoalbuminemia; hyperlipidemia; andlipiduria. In a specific embodiment, the present invention providesmethods of treating paroxysmal nocturnal hemoglobinuria (PNH) byadministering to a subject in need thereof an effective amount of acomposition comprising an antibody of the present invention.

In a specific embodiment, the present invention provides methods ofreducing the dysfunction of the immune and hemostatic systems associatedwith extracorporeal circulation by administering to a subject in needthereof an effective amount of a composition comprising an antibody ofthe present invention. The antibodies of the present invention can beused in any procedure which involves circulating the patient's bloodfrom a blood vessel of the patient, through a conduit, and back to ablood vessel of the patient, the conduit having a luminal surfacecomprising a material capable of causing at least one of complementactivation, platelet activation, leukocyte activation, orplatelet-leukocyte adhesion. Such procedures include, but are notlimited to, all forms of ECC, as well as procedures involving theintroduction of an artificial or foreign organ, tissue, or vessel intothe blood circuit of a patient.

Subjects to be treated with therapeutic agents of the present inventioncan also be administered other therapeutic agents with know methods oftreating conditions associated with macular degeneration, such asantibiotic treatments as described in U.S. Pat. No. 6,218,368. In othertreatments, immunosuppressive agents such as cyclosporine, are agentscapable of suppressing immune responses. These agents include cytotoxicdrugs, corticosteriods, nonsteroidal anti-inflammatory drugs (NSAIDs),specific T-lymphocyte immunosuppressants, and antibodies or fragmentsthereof (see Physicians' Desk Reference, 53rd edition, Medical EconomicsCompany Inc., Montvale, N.J. (1999). Immunosuppressive treatment istypically continued at intervals for a period of a week, a month, threemonths, six months or a year. In some patients, treatment isadministered for up to the rest of a patient's life.

When the therapeutic agents of the present invention are administeredtogether with another agent, the two can be administered sequentially ineither order or simultaneously. In some aspects, an antibody of thepresent invention is administered to a subject who is also receivingtherapy with a second agent (e.g., verteporfin). In other aspects, thebinding molecule is administered in conjunction with surgicaltreatments.

Suitable agents for combination treatment with Factor P bindingantibodies include agents known in the art that are able to modulate theactivities of complement components (see, e.g., U.S. Pat. No.5,808,109). Other agents have been reported to diminishcomplement-mediated activity. Such agents include: amino acids (Takada,Y. et al. Immunology 1978, 34, 509); phosphonate esters (Becker, L.Biochem. Biophy. Acta 1967, 147, 289); polyanionic substances (Conrow,R. B. et al. J. Med. Chem. 1980, 23, 242); sulfonyl fluorides (Hansch,C.; Yoshimoto, M. J. Med. Chem. 1974, 17, 1160, and references citedtherein); polynucleotides (DeClercq, P. F. et al. Biochem. Biophys. Res.Commun. 1975, 67, 255); pimaric acids (Glovsky, M. M. et al. J. Immunol.1969, 102, 1); porphines (Lapidus, M. and Tomasco, J. Immunopharmacol.1981, 3, 137); several antiinflammatories (Burge, J. J. et al. J.Immunol. 1978, 120, 1625); phenols (Muller-Eberhard, H. J. 1978, inMolecular Basis of Biological Degradative Processes, Berlin, R. D. etal., eds. Academic Press, New York, p. 65); and benzamidines (Vogt, W.et al Immunology 1979, 36, 138). Some of these agents function bygeneral inhibition of proteases and esterases. Others are not specificto any particular intermediate step in the complement pathway, but,rather, inhibit more than one step of complement activation. Examples ofthe latter compounds include the benzamidines, which block C1, C4 andC3b utilization (see, e.g., Vogt et al. Immunol. 1979, 36, 138).

Additional agents known in the art that can inhibit activity ofcomplement components include K-76, a fungal metabolite fromStachybotrys (Corey et al., J. Amer. Chem. Soc. 104: 5551, 1982). BothK-76 and K-76 COOH have been shown to inhibit complement mainly at theC3b step (Hong et al., J. Immunol. 122: 2418, 1979; Miyazaki et al.,Microbiol. Immunol. 24: 1091, 1980), and to prevent the generation of achemotactic factor from normal human complement (Bumpers et al., Lab.Clinc. Med. 102: 421, 1983). At high concentrations of K-76 or K-76COOH, some inhibition of the reactions of C2, C3, C6, C7, and C9 withtheir respective preceding intermediaries is exhibited. K-76 or K-76COOH has also been reported to inhibit the C3b inactivator system ofcomplement (Hong et al., J. Immunol. 127: 104-108, 1981). Other suitableagents for practicing methods of the present invention includegriseofulvin (Weinberg, in Principles of Medicinal Chemistry, 2d Ed.,Foye, W. O., ed., Lea & Febiger, Philadelphia, Pa., p. 813, 1981),isopannarin (Djura et al., Aust. J. Chem. 36: 1057, 1983), andmetabolites of Siphonodictyon coralli-phagum (Sullivan et al.,Tetrahedron 37: 979, 1981).

A combination therapy regimen may be additive, or it may producesynergistic results (e.g., reductions in complement pathway activitymore than expected for the combined use of the two agents). In someembodiments, the present invention provide a combination therapy forpreventing and/or treating AMD or another complement related disease asdescribed above with a Factor P binding antibody of the invention and ananti-angiogenic, such as anti-VEGF agent, or another anti-complementantibody such as an antibody or antigen binding fragment thereof thatbinds to complement factor 5 (C5).

Combination of Anti-Complement Antibodies

In one aspect, the invention provides combinations of any one or more ofthe anti-Factor P with an additional antibody that binds to and inhibitsthe activity of a different component of the complement pathway. Inparticular, the invention includes any one or more of the anti-Factor Pantibodies or antigen binding fragments described herein in combinationwith an antibody or antigen binding fragment that binds complementcomponent 5 (C5). Examples of antibodies or antigen binding fragmentsthereof that bind to C5 and inhibit complement activation can be found,for example in U.S. Pat. No. 8,241,628 (incorporated herein byreference). More specifically, antibodies or antigen binding fragmentsthereof that bind to C5 and inhibit the complement pathway are shown anddescribed in Table 2. In one aspect the invention includes a combinationof an anti-Factor P antibody or antigen binding fragment thereof asshown and described in Table 1 with the anti-C5 antibody 8109 from Table2. More specifically, one aspect of the invention relates to acombination of antibody NVS962 from Table 1 (or an antigen bindingfragment thereof) with antibody 8109 from Table 2 (or an antigen bindingfragment thereof).

In one aspect the combinations of anti-Factor P and anti-C5 antibodiesdescribed herein demonstrate a syntergistic inhibition of the complementpathway, particularly the alternative complement pathway. Suchinhibition can be demonstrated, for example, using the hemolytic orpoly-IC assays described in the Examples below. Synergy in theinhibition of the alternative complement pathway, achieved using acombination of the anti-Factor-P and anti-C5 antibodies described hereincan be determined using methods that are well known in the art. Forexample, a synergistic effect of the combination of anti-Factor Pantibody and anti-C5 antibody can be determine relative to a merelyadditive effect using specific software, such as a Chalice Analyzer.

Briefly, Chalice Analyzer (Lehar et al, Nature Biotechnology 2009,7:659) software can be used to determine whether the combination ofcomplement inhibiting antibodies (e.g., anti-Factor P and anti-C5) actedsynergistically to block complement activation. Combination effects canbe characterized by comparing each data point's inhibition to that of acombination reference model that was derived from the single agentcurves (Greco, Bravo, Parsons (1995). The search for synergy: a criticalreview from a response surface perspective. Pharmacol Rev 47(2):331-85). In the Loewe additivity model (Loewe (1928). Die quantitativenProbleme der Pharmakologie. Ergebn. Physiol. 27: 47-187),I_(Loewe)(C_(X),C_(Y)) is the inhibition that satisfies (C_(X)/C_(X))(C_(Y)/C_(Y))=1, and IC_(X,Y) are the effective concentrations atI_(Loewe) for the fitted single agent curves. Loewe additivity is thegenerally accepted reference for synergy (Greco et al.), as itrepresents the combination response generated if X and Y are the samecompound.

Potency shifting is usually shown using an isobologram (Greco et al.)which shows how much less drug is required in combination to achieve adesired effect level, when compared to the single agent doses needed toreach that effect. The choice of effect level for the isobologramdisplay and combination index calculations can either be manually orautomatically selected in the Chalice Analyzer. The automatic iso-levelselection algorithm finds the observed I_(data) with the largestI_(data)−I_(Loewe), excluding those points with I_(data) exceeding thelesser single agent's I_(max). This exclusion is applied to ensure thatthe isobologram reflects the best synergy at levels covered by bothsingle agents. Having selected an isobologram level I_(cut), theisobologram is drawn by identifying the locus of concentrations thatcorrespond to crossing the chosen iso-level. The isobologram shows thestandard isobolographic analysis of synergy compared to the Loewedose-additive “drug-with-itself” standard. For a specified isobologramlevel, the observed iso-effect contour (e.g., curved line in FIG. 3) isdisplayed with the theoretical dose-additive contour (e.g., straightline in FIG. 3), on an IC_(effect)-normalized linear concentration scalefor both substances in the combination. The Dose-additive reference isalways a line connecting the two IC_(effect) concentrations. TheIC_(effect) crossing points are found by interpolating the fittedsigmoidal dose response curves.

Potency shifting is scored as the combination index (Chou, Talalay(1984). Quantitative analysis of dose-effect relationships: the combinedeffects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27-55) CI. For a chosen iso-effect level I_(cut),CI_(I)=(C_(X)/EC_(X))_(I)+(C_(Y)/EC_(Y))_(I), where (C_(X)/EC_(X))_(I)for a particular data point is the ratio of the X compound's measuredconcentration to its effective concentration at the chosen inhibitionlevel. The CI can be thought of as a rough estimate of how much drug wasneeded in combination relative to the single agent doses required toachieve the chosen effect level, and a value of 0.1 means that only atenth of equivalent amounts of the single agents were needed for thecombination to reach the same effect level. CI values in the range of0.5-0.7 are typical for in vitro measurements of current clinicalcombinations (Greco et al.). A CI value of 1.0 is indicative of anadditive effect of a combination of antibodies, while a CI value of lessthan 0.5 is indicative of a strong synergistic effect resulting from theantibody combination. In the Chalice Analyzer, the best CI is reportedfrom the many combination index values calculated for each I_(cut)crossing concentration. Among all the measured CI values, the one withthe largest signal-to-noise level is reported as the best combinationindex.

Combinations of anti-Factor P and anti-C5 antibodies as described hereincan be administered singly or as a single composition. In addition, therelative dose of an anti-Factor P and anti-C5 antibody can be in a ratioof 1:1, or may be in a different ratio. The specific dose of ananti-Factor P antibody relative to an anti-C5 antibody may ultimately bedetermined by a treating physician or health care professional toachieve improvement in the pathological condition being treated. Forexample, when a combination as described herein is used to treat AMD, aphysician or health care professional may taylor the relative doses ofthe anti-Factor P and anti-C5 antibodies so as to achieve optimaltherapeutic benefit as determined using the measurements and criteriadescribed herein.

Pharmaceutical Compositions

The invention provides pharmaceutical compositions comprising the FactorP-binding antibodies (intact or binding fragments) formulated togetherwith a pharmaceutically acceptable carrier. The compositions canadditionally contain one or more other therapeutic agents that aresuitable for treating or preventing, for example, pathologicalangiogenesis or tumor growth. Pharmaceutically acceptable carriersenhance or stabilize the composition, or can be used to facilitatepreparation of the composition. Pharmaceutically acceptable carriersinclude solvents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents, and the likethat are physiologically compatible.

A pharmaceutical composition of the present invention can beadministered by a variety of methods known in the art. The route and/ormode of administration vary depending upon the desired results. It ispreferred that administration be intravitreal, intravenous,intramuscular, intraperitoneal, or subcutaneous, or administeredproximal to the site of the target. The pharmaceutically acceptablecarrier should be suitable for intravitreal, intravenous, intramuscular,subcutaneous, parenteral, spinal or epidermal administration (e.g., byinjection or infusion). Depending on the route of administration, theactive compound, i.e., antibody, bispecific and multispecific molecule,may be coated in a material to protect the compound from the action ofacids and other natural conditions that may inactivate the compound.

The composition should be sterile and fluid. Proper fluidity can bemaintained, for example, by use of coating such as lecithin, bymaintenance of required particle size in the case of dispersion and byuse of surfactants. In many cases, it is preferable to include isotonicagents, for example, sugars, polyalcohols such as mannitol or sorbitol,and sodium chloride in the composition. Long-term absorption of theinjectable compositions can be brought about by including in thecomposition an agent which delays absorption, for example, aluminummonostearate or gelatin.

Pharmaceutical compositions of the invention can be prepared inaccordance with methods well known and routinely practiced in the art.See, e.g., Remington: The Science and Practice of Pharmacy, MackPublishing Co., 20th ed., 2000; and Sustained and Controlled ReleaseDrug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., NewYork, 1978. Pharmaceutical compositions are preferably manufacturedunder GMP conditions. Typically, a therapeutically effective dose orefficacious dose of the Factor P-binding antibody is employed in thepharmaceutical compositions of the invention. The Factor P-bindingantibodies are formulated into pharmaceutically acceptable dosage formsby conventional methods known to those of skill in the art. Dosageregimens are adjusted to provide the optimum desired response (e.g., atherapeutic response). For example, a single bolus may be administered,several divided doses may be administered over time or the dose may beproportionally reduced or increased as indicated by the exigencies ofthe therapeutic situation. It is especially advantageous to formulateparenteral compositions in dosage unit form for ease of administrationand uniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the subjects tobe treated; each unit contains a predetermined quantity of activecompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of the present invention can be varied so as to obtain anamount of the active ingredient which is effective to achieve thedesired therapeutic response for a particular patient, composition, andmode of administration, without being toxic to the patient. The selecteddosage level depends upon a variety of pharmacokinetic factors includingthe activity of the particular compositions of the present inventionemployed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound being employed, the duration of the treatment, otherdrugs, compounds and/or materials used in combination with theparticular compositions employed, the age, sex, weight, condition,general health and prior medical history of the patient being treated,and like factors.

A physician or veterinarian can start doses of the antibodies of theinvention employed in the pharmaceutical composition at levels lowerthan that required to achieve the desired therapeutic effect andgradually increase the dosage until the desired effect is achieved. Ingeneral, effective doses of the compositions of the present invention,for the treatment of an allergic inflammatory disorder described hereinvary depending upon many different factors, including means ofadministration, target site, physiological state of the patient, whetherthe patient is human or an animal, other medications administered, andwhether treatment is prophylactic or therapeutic. Treatment dosages needto be titrated to optimize safety and efficacy. For systemicadministration with an antibody, the dosage ranges from about 0.0001 to100 mg/kg, and more usually 0.01 to 15 mg/kg, of the host body weight.For intravitreal administration with an antibody, the dosage may rangefrom 0.1 mg/eye to 5 mg/eye. For example, 0.1 mg/ml, 0.2 mg/ml, 0.3mg/ml, 0.4 mg/ml, 0.5 mg/ml, 0.6 mg/ml, 0.7 mg/ml, 0.8 mg/ml, 0.9 mg/ml,1.0 mg/ml, 1.1 mg/ml, 1.2 mg/ml, 1.3 mg/ml, 1.4 mg/ml, 1.5 mg/ml, 1.6mg/ml, 1.7 mg/ml, 1.8 mg/ml, 1.9 mg/ml, 2.0 mg/ml, 2.1 mg/ml, 2.2 mg/ml,2.3 mg/ml, 2.4 mg/ml, 2.5 mg/ml, 2.6 mg/ml, 2.7 mg/ml, 2.8 mg/ml, 2.9mg/ml, 3.0 mg/ml, 3.1 mg/ml, 3.2 mg/ml, 3.3 mg/ml, 3.4 mg/ml, 3.5 mg/ml,3.6 mg/ml, 3.7 mg/ml, 3.8 mg/ml, 3.9 mg/ml, 4.0 mg/ml, 4.1 mg/ml, 4.2mg/ml, 4.3 mg/ml, 4.4 mg/ml, 4.5 mg/ml, 4.6 mg/ml, 4.7 mg/ml, 4.8 mg/ml,4.9 mg/ml, or 5.0 mg/ml. An exemplary treatment regime entails systemicadministration once per every two weeks or once a month or once every 3to 6 months. An exemplary treatment regime entails systemicadministration once per every two weeks or once a month or once every 3to 6 months

Antibody is usually administered on multiple occasions. Intervalsbetween single dosages can be weekly, monthly or yearly. Intervals canalso be irregular as indicated by measuring blood levels of FactorP-binding antibody in the patient. In addition alternative dosingintervals can be determined by a physician and administered monthly oras necessary to be efficacious. Efficacy is based on lesion growth, rateof Lucentis rescue, retinal thickness as determined by SpectralDomain-optical Optical Coherence Tomography (SD-OCT), and secondaryvisual acuity. In some methods of systemic administration, dosage isadjusted to achieve a plasma antibody concentration of 1-1000 μg/ml andin some methods 25-500 μg/ml. Alternatively, antibody can beadministered as a sustained release formulation, in which case lessfrequent administration is required. Dosage and frequency vary dependingon the half-life of the antibody in the patient. In general, humanizedantibodies show longer half life than that of chimeric antibodies andnonhuman antibodies. The dosage and frequency of administration can varydepending on whether the treatment is prophylactic or therapeutic. Inprophylactic applications, a relatively low dosage is administered atrelatively infrequent intervals over a long period of time. Somepatients continue to receive treatment for the rest of their lives. Intherapeutic applications, a relatively high dosage at relatively shortintervals is sometimes required until progression of the disease isreduced or terminated, and preferably until the patient shows partial orcomplete amelioration of symptoms of disease. Thereafter, the patientcan be administered a prophylactic regime.

EXAMPLES

The following examples are provided to further illustrate the inventionbut not to limit its scope. Other variants of the invention will bereadily apparent to one of ordinary skill in the art and are encompassedby the appended claims.

Example 1 Generation of Affinity Matured Factor P Antibodies

A fully human phage display library was used to generate the Factor Pbinding antibodies described herein.

Biotinylated and non-biotinylated human and cynomolgus Factor P wereused in solution and solid phase pannings. Standard panning wereperformed as well as RapMAT approaches (Prassler et al., (2009)Immunotherapy 1(4):571-583). Following affinity maturation (Knappik etal., (2000) J. Mol. Biol., 296:57-86) a set of 10 antibodies weresubsequently chosen for conversion to a disulfide-bridged Fab format.The resulting disulfide bridged Fabs are shown in Table 1 (NVS962,NVS963, NVS964, NVS965, NVS966, NVS967).

Example 2 Further Antibody Optimization

The following example describes methods that may be used to furtheroptimize antibodies described herein.

Removal of Deamidation Sites

Deamindation sites were identified by peptide mapping and size exclusionchromatography (SEC), run under reducing conditions. The deamidatedmaterial has decreased potency in a MAC deposition assay and decreasedaffinity for human and cyno FP as measured by Biacore and SET. Theextent of deamidation increased over time (3 weeks), at highertemperatures (5 days at 37 C), and under reducing conditions.Deamidation can be detected using an ion-exchange column resultingmultiple peaks and observation of the additional, deamidated peak. Aminoacid sequences that are most prone to deamidation are: SNG, LNG, LNN,ELN (Daugherty, A. and Mrsny, R. (2010) Current Trends in MonoclonalAntibody Development and Manufacturing. Springer. p 103-129.).Accordingly, we engaged in a series of studies to remove the deamidationsites and test the modified antibodies for retained function.

Two Fabs, NVS962 and NVS965, were re-engineered to replace adeamindation site on the heavy chain, specifically occurring at anasparagine at position 30. The following new Fabs were generated toremove the deamindation site and corresponding amino acid replacementsshown in Table 2.

TABLE 2 Deamidated Fabs Deaminadated Fab N30 replaced with: Modified FabNVS962 Serine NVS962-S Glutamine NVS962-Q Glycine NVS962-G ThreonineNVS962-T NVS965 Threonine NVS965-T Glutamine NVS965-Q Serine NVS965-S

An additional Fab that was generated replaced serine 31 with an alaninein Fab NVS962, generating Fab NVS962-S31A. The sequences of the modifiedFabs is shown in Table 1.

Removal of Cleavage Sites

Further optimization was conducted on NVS962-S and NVS965-S to remove acleavage site in the heavy chain CDR3. Specifically the heavy chain wascleaved at Y102S103. The following table describes the amino acidsubstitutions that were made to destroy the cleavage site. The sequencesof the modified Fabs is shown in Table 1.

TABLE 3 Modified Fabs Clipped Fab Y102 replaced with: S103 replacedwith: Modified Fab NVS962-S F I NVS808 K V NVS806 S Y NVS807 NVS965-S YI NVS804 Y V NVS805 Y Y NVS809

Example 3 Characterization of Optimized Antibodies

The following example describes methods that may be used to measureantibody affinity. These and other methods of measuring binding affinityare known in the art.

Affinity Determination

Antibody affinity for Factor P was measured by surface plasmon resonance(SPR) using a Biacore T200 (Biacore) and solution equilibrium titration(SET). Explanations of each technology and corresponding mean resultsfor Factor P binding are described below. Modelling assumptions takeinto account concentrations of Factor P in the system, kinetics ofFactor P biosynthesis and half-life, as well as the desired dosingschedule, and suggest that a Fab with an affinity of greater than 500 pMfor Factor P is sufficient to lower levels of free Factor P.

Biacore Determination

The kinetics of an interaction, i.e. the rates of complex formation(k_(a)) and dissociation (k_(a)), can be determined from the informationin a sensorgram. If binding occurs as sample passes over a preparedsensor surface, the response in the sensorgram increases. If equilibriumis reached a constant signal will be seen. Replacing sample with buffercauses the bound molecules to dissociate and the response decreases.Biacore evaluation software generates the values of k_(a) and k_(d) byfitting the data to interaction models (Table 4).

Biacore kinetic experiments were done with the BIAcore T100 (GEHealthcare) using CM5 sensor chips (GE Healthcare, BR-1005-30) at 25° C.The running buffer was HBS-EP(+) (GE Healthcare, BR-1001-88). Briefly,the following steps were carried out to determine binding affinity.

-   -   Prepare anti-FP IgG immobilized sensor chip: Mouse anti-FP        monnoclonal antibody (Quidel, A235) (30 ug/ml in acetate pH5.0        coupling buffer (GE Healthcare, BR-1003-51)) was coupled to two        different flow cells (Fc1 and 2) on a CM5 chip at 10 ul/min flow        rate for 600 seconds by using amino-coupling procedure according        to the supplier's instruction (GE Healthcare, BR-1000-50). The        final immobilized level will be >7000RU.    -   Capture FP on second flow cell: 1 ug/ml of FP in running buffer        was injected at 10 ul/min on second flow cell (Fc2) to reach        capture level ˜20 RU for Fab or −7 RU for IgG kinetics analysis.    -   Inject anti-FP Fab or IgG at different concentration on both        flow cells: Inject anti-FP solution (0.3125 nM-10 nM in running        buffer; at 1:2 serial dilutions) on both flow cells (Fc1 and 2)        at 60 ul/min for 240 seconds.    -   Dissociation: Inject HBS-EP(+) running buffer at 60 ul/min on        both flow cells to monitor the dissociation between FP and        anti-FP Fab/IgG. Dissociation time was set at 2400 seconds for 5        nM and 2.5M Fab/IgG concentrations and at 300 seconds for all        other concentrations including another 5 nM Fab/IgG        concentration.    -   Regeneration: Regeneration was performed at the end of each        cycle on both flow cells with 10 mM Glycine-HCl pH1.7 (provided        by GE Healthcare)+0.05% P20 surfactant (GE Healthcare,        BR-1000-54) at a flow rate of 60 ul/min for 15 seconds twice.    -   Kinetics analysis: Kinetic rate constants was obtained by        applying 1:1 binding model with BIAevaluation 1.1 software,        wherein the Rmax values were fit locally.

The results of the Biacore binding kinetics determination are shown inTable 4. As shown the antibodies described herein exhibit high affinitybinding to human Factor P, with KD values typically less than or equalto 1 nM, and in many cases less than or equal to 200 pM. Theseantibodies also show very high affinity to cyno Factor P (bindingaffinity less than 500 pM).

SET Determination

In contrast to kinetic assays using sensor surfaces, such as SPR, SET isa method which determines affinities in solution. It is an equilibriummeasurement that does not deliver kinetic data.

In SET, a constant amount of antibody is incubated with differentconcentrations of antigen until equilibrium is reached. Theconcentration of free antibody in the equilibrated solution isdetermined by applying the solution on an antigen coated MSD™ plate(Meso Scale Discovery™) followed by incubation with an ECL-labeledsecondary antibody and measurement of signal intensity. At low antigenconcentrations, a strong signal is achieved (high concentration of freeantibody which binds to the antigen on the plate) whereas for highantigen concentration, the antibody is completely antigen-captured,resulting in a low signal. If a sufficient number of antigenconcentrations in a matching range are available, the titration curveallows for a reasonable determination of the affinity, using theappropriate fit model. For a complete titration, antigen concentrationsof at least 10-fold higher than the anticipated K_(D) have to beapplied. The constant concentration of antibody applied in the assayshould be in the range of, or below, the K_(D) (Table 4).

For K_(D) determination by solution equilibrium titration (SET), monomerfractions of antibody protein were used (at least 90% monomer content,analyzed by analytical SEC; Superdex75 (Amersham Pharmacia) for Fab, orTosoh G3000SWXL (Tosoh Bioscience) for IgG, respectively).

Affinity determination in solution was basically performed as describedin the literature (Friguet et al. 305-19). In order to improve thesensitivity and accuracy of the SET method, it was transferred fromclassical ELISA to ECL based technology (Haenel et al., 2005).

1 mg/ml goat-anti-human (Fab)₂ fragment specific antibodies (Dianova)were labeled with MSD Sulfo-TAG™ NHS-Ester (Meso Scale Discovery,Gaithersburg, Md., USA) according to the manufacturers instructions.

Human Factor P (Complement Technology cat#: A139) and Cyno Factor Ppurified from cyno serum (protocol adapted from Nakano, et al., (1986) JImmunol Methods 90:77-83) were coated on standard binding MSD plates(Meso-Scale Discovery, 384-well: MSD cat#: L21XA, 96-well: MSD cat#:L15XA) at 0.2-0.3 μg/ml in 25 μl PBS and incubated overnight at 4° C.Factor P inhibitors were diluted to a fixed concentration (1 pM or 10pM) in incubation buffer (PBS with 2% BSA (Sigma cat#: A4503) and 1%Tween20 and 1% Triton-X (Sigma cat#: 234729)), and added to a serialdilution of Factor P (human or cyno) in incubation buffer. Samples wereallowed to reach equilibrium by incubation at RT overnight. Plates werewashed 3× in wash buffer (PBS with 0.05% Tween20), and blocked with 100μl incubation buffer at RT for 2 hrs. Plates were washed 3× in washbuffer. Sample containing Factor P inhibitors and Factor P titrationwere added to the plate (25 μl), and incubated at RT for 15 min. Plateswere washed 3× in wash buffer. 25 μl detection antibody was added(Anti-Human (Goat) Sulfo-TAG, 1:1000 in incubation buffer, MSD cat#:R32AJ-1), and incubated at RT for 60 min. Plates were washed 3× in washbuffer, and 50 μl of 1×MSD Read buffer T was added (with surfactant, MSDcat#: R92TC-1). Plates were read on a MSD Spector Imager 6000. Data wasanalyzed using GraphPad Prism software v4, with background (an averageof wells containing no Fab) subtracted from each value. X-axis values(concentration of Factor P in solution) were transformed into log 10x.KD values (KD) were fitted from the following model:

Fab:

Y=(Top−((Top/(2×Fab))×((((10̂x)+Fab)+KD)−(((((10̂x)+Fab)+KD)×(((10̂x)+Fab)+KD))−((4×(10̂x))×Fab))̂0.5))))

Top=signal at antigen concentration=0x=concentration of Factor P in solutionFab=concentration of applied monovalent analyte (Fab)

TABLE 4 Affinity Binding of Factor P Antibodies SET Biacore BiacoreBiacore Factor P Factor P K_(D) K_(D) K_(a) Kd Antibody Species (pM)(pM) (1/Ms) (1/s) NVS962 Human 46 83 1.52 × 10⁶ 1.25 × 10⁻⁴ Cyno 47 1821.53 × 10⁶ 2.79 × 10⁻⁴ NVS965 Human 36 16 2.65 × 10⁶ 4.10 × 10⁻⁵ Cyno 1428 2.24 × 10⁶ 6.22 × 10⁻⁵ NVS963 Human 55 90   1 × 10⁶   1 × 10⁻⁴ Cyno115 170   1 × 10⁶   2 × 10⁻⁴ NVs966 Human 70 160   2 × 10⁶   3 × 10⁻⁴Cyno 40 210   1 × 10⁵   2 × 10⁻⁴ NVS964 Human 20 35   1 × 10⁶   4 × 10⁻⁵Cyno 190 160   1 × 10⁶   2 × 10⁻⁴ NVS967 Human 40 60   1 × 10⁶   9 ×10⁻⁵ Cyno 280 315   1 × 10⁶   6 × 10⁻⁴ NVS962-Q Human 1061 496 6.27 ×10⁵ 3.11 × 10⁻⁴ Cyno 930 475 5.55 × 10⁵ 2.64 × 10⁻⁴ NVS962-S Human 156161  7.3 × 10⁵ 1.17 × 10⁻⁴ Cyno 141 127 5.24 × 10⁵ 6.66 × 10⁻⁵ NVS962-THuman 251 131 6.39 × 10⁵ 8.35 × 10⁻⁵ Cyno 354 175 4.88 × 10⁵ 8.56 × 10⁻⁵NVS962-G Human 953 1140 3.87 × 10⁵  4.4 × 10⁻⁴ Cyno 567 1080 3.13 × 10⁵3.39 × 10⁻⁴ NVS962-S31A Human 189 225 5.04 × 10⁵ 1.13 × 10⁻⁴ Cyno 189234 3.72 × 10⁵  8.7 × 10⁻⁵ NVS965-Q Human 301 138 2.65 × 10⁶ 3.66 × 10⁻⁴Cyno 201 215 2.77 × 10⁶ 5.94 × 10⁻⁴ NVS965-S Human 51 27 3.69 × 10⁶  9.9× 10⁻⁵ Cyno 36 60 2.71 × 10⁶ 1.63 × 10⁻⁴ NVS965-T Human 52 51.4 2.37 ×10⁶ 1.03 × 10⁻⁴ Cyno 44 74.6 2.17 × 10⁶ 1.51 × 10⁻⁴ NVS808 Human 107 1957.91 × 10⁵ 1.54 × 10⁻⁴ Cyno ND ND ND ND NVS806 Human 18 52 4.34 × 10⁵2.24 × 10⁻⁵ Cyno ND ND ND ND NVS807 Human 27 106 1.21 × 10⁶ 1.23 × 10⁻⁴Cyno ND ND ND ND NVS804 Human 0.8 5 2.72 × 10⁶ 1.29 × 10⁻⁵ Cyno ND ND NDND NVS805 Human 0.3 3 3.61 × 10⁶ 9.88 × 10⁻⁶ Cyno ND ND ND ND NVS809Human 4.2 24.7 4.25 × 10⁶ 1.04 × 10⁻⁴ Cyno ND ND ND ND

Example 4 Factor P Antibodies Inhibit the Alternative Complement PathwayHemolysis Assay

In hemolytic techniques, all of the complement components must bepresent and functional. Therefore hemolytic techniques can screen bothfunctional integrity and deficiencies of the complement system (van etal., 1980; Minh et al., 1983; Tanaka et al., 1986). To measure thefunctional capacity of the classical pathway, sheep red blood cellscoated with hemolysin (rabbit IgG to sheep red blood cells) or chickenred blood cells that are sensitized with rabbit anti-chicken antibodiesare used as target cells (sensitized cells). These Ag-Ab complexesactivate the classical pathway and result in lysis of the target cellswhen the components are functional and present in adequateconcentration. To determine the functional capacity of the alternativepathway in human and cynomolgus sera, rabbit red blood cells are used asthe target cell (see U.S. Pat. No. 6,087,120).

The hemolytic assay is a basic functional assay that tests forcomplement activation and has been used to evaluate the ability ofanti-human FP mAbs and Fab molecules to block lysis of red blood cells(RBCs) by complement pathways. In vitro and in vivo inhibition ofcomplement activity by a single-chain Fv fragment recognizing human C5can be measured using a haemolytic assay (Thomas et al., 1996; Rinder etal., 1995; Rinder et al., 1995). Blockade of C5a and C5b-9 generationinhibits leukocyte and platelet activation during extracorporealcirculation. Briefly, for classical pathway assays, sensitized red bloodcells (e.g., chicken RBCs) are used as targets for lysis by complementproteins present in serum. The following assay is of interest for thecharacterization and screening of Factor P antibodies for theirinhibition of the alternative complement pathway.

This procedure was adapted from (Rinder et al., 1995; Thomas et al.,1996).

Reagents:

-   -   Rabbit red blood cells (Rb RBCs)—Lampire, Cat#7246408    -   Human serum Novartis Blood Research Program; or Cyno serum Alpha        Genesis    -   Gelatin veronal buffer (GVB) Boston BioProducts, Cat# IBB-300    -   EGTA Boston BioProducts, Cat# BM-151    -   MgCl2    -   U-bottom 96-well plate Corning, Cat#3795    -   Flat-bottom 96-well plate Corning, Cat#3370    -   NP-40 Sigma, Cat#74385

Protocol:

Rabbit red blood cells (RBCs) were washed and adjusted to 8.33×10⁷cells/ml in GVB/EGTA/Mg++. 50 μl Fab diluted in GVB was added to wellsin a 96-well round bottom plate. 50 μl serum diluted in GVB with EGTAand Mg++ was then added. Control wells were prepared in the followingmanner: serum without Fab (negative control) and cells plus 0.1% NP-40(100% lysis control), and NP-40 blank wells. Serum with and without Faband controls were incubated at room temperature for 30 minutes. At thatpoint, 30 μl Rb RBCs were added to sample and control wells and 30 μl ofbuffer was added to the blank wells. The cells were generally incubatedfor 30 minutes at 37° C. and the plate centrifuged at 2000 rpm for 5min. The supernatant was harvested and transferred to a flat-bottomplate. The absorbance of the supernatant was read at OD415 and OD570.Percent hemolysis was calculated using the formula below.

${\% \mspace{14mu} {Hemolysis}} = \frac{\begin{matrix}{\left( {{ODsample}\mspace{14mu} - {{ODserum} \cdot {blank}}} \right) -} \\\left( {{{OD}\mspace{14mu} 0\% \mspace{14mu} {lysis}} - {{ODbuffer} \cdot {blank}}} \right)\end{matrix}}{\begin{matrix}{\left( {{{OD}\mspace{14mu} 100\% \mspace{14mu} {lysis}} - {{ODNP}\mspace{14mu} {40 \cdot {blank}}}} \right) -} \\\left( {{{OD}\mspace{14mu} 0\% \mspace{14mu} {lysis}} - {{ODbuffer}\mspace{14mu} {40 \cdot {blank}}}} \right)\end{matrix}}$

Table 5 exemplifies of the ability of the Factor P antibodies andantigen binding fragments to inhibit hemolysis in 10% human or 20%cynomolgus serum. Each of the Factor P antibodies described hereininhibited hemolysis with an 1050 of less than or equal to 50 nM.

In contrast, when the assay was performed using sensitized red bloodcells in order to examine activation of the classical complementpathway, the Factor P antibodies described herein were found not toinhibit the classical complement pathway (data not shown).

C3b Deposition Assay

One method of measuring the inhibitor activity against the complement C3in the alternative pathway is to measure its breakdown product, C3b,depositing on zymosan. This ELISA based assay was performed according tothe following steps: 25 μl of 1 mg/ml Zymosan A (Sigma Z4250) incarbonate buffer, pH 9.6 (Pierce Cat#28382) was coated on Maxisorp384-well ELISA plate (Nunc 464718) overnight at 4° C. On the followingday, the zymosan-coated plate was aspirated and blocked with 100 μl perwell of ELISA blocking buffer, Synblock (AbD Serotec BUFO34C) for 2 h atroom temperature. In a separate reaction, the inhibitors, seriallydiluted in gelatin veronal buffer (Boston Bioproducts IBB320-10 mMBarbital, 145 mM NaCl, 0.1% Gelatin, 0.5 mM MgCl₂, 10 mM EGTA) wereadded to 10% serum supplemented with MgCl₂ and EGTA for a final totalreaction concentration of 1 mM MgCl₂ and 10 mM EGTA. The positivecontrol contained no inhibitor and negative control had 25 mM EDTA. Themixture was allowed to reach equilibrium by incubating at roomtemperature for 30 min. To remove the blocking buffer, the buffer wasaspirated and the plate was washed once with TBS/0.05% Tween-20. 25 μlper well of the 10% serum containing the inhibitors or controls wasadded to the plate and incubated at 37° C. for 30 min (previouslydetermined by time-course to be within the linear range of C3bdeposition on zymosan.) After the 30 min incubation, the plate waswashed three times with TBS/0.05% Tween-20. To detect C3b deposition onzymosan, 25 μl per well of chicken anti-human C3-HRP conjugatedpolyclonal antibody (Immunology Consultants Laboratory, Inc. Cat#CC3-80P-1) diluted according to manufacturer in PBS with 2% BSA FractionV (Fisher Cat# ICN 16006980), 0.1% Tween20 (Sigma Cat# P1379), and 0.1%TritonX-100 (Sigma Cat# P234729) was added to the plate and incubate atroom temperature for 1 h. Afterward, the plate was washed three timeswith TBS/0.05% Tween-20 and then add 25 μl of Ultra TMB SubstrateSolution (Pierce Cat#34028.) When the solution in the well turned blue,the reaction was stopped with 15 μl of 2N sulfuric acid. The plate wasread at 450 nm using the Spectromax with correction for the plasticplate at 570 nm (OD_(450-570 nm) reading.) The percentage of C3bdeposition on zymosan was calculated using the following formula:

${\% \mspace{20mu} C\; 3b\mspace{14mu} {Deposition}} = {100 - {100*\frac{\begin{bmatrix}{\left( {{OD}_{{no}\mspace{11mu} {inhibitor}} - {OD}_{25\; {mM}\mspace{14mu} {EDTA}}} \right) -} \\\left( {{OD}_{sample} - {OD}_{25{mM}\mspace{14mu} {EDTA}}} \right)\end{bmatrix}}{\left( {{OD}_{{no}\mspace{14mu} {inhibitor}} - {OD}_{25{mM}\mspace{14mu} {EDTA}}} \right)}}}$

Each of the antibodies tested were shown to inhibit C3b deposition withan 1050 of at least less than or equal to 10 nM (Table 5).

MAC Deposition Assay

Another assay that was used to determine the ability of the Factor Pantibodies to inhibit the alternative complement pathway was to measurethe ability of the antibodies to inhibit the generation of the membraneattack complex (MAC), which is downstream of the C3 convertase and theactivity of Factor P. Briefly, Zymosan A (Sigma) was coated on a plateat 1 mg/ml in carbonate buffer, pH 9.5, to activate the AlternativePathway. Fabs were pre-incubated with serum (20% serum, 5 mM MgCl₂, 10mM EDTA), then added to the plate and incubated overnight at roomtemperature. After washing the plate three times with TBST, MAC wasdetected by incubation with anti-C5b-9-ALP (Diatec) for 1 h, followed bythree washes with TBST, and incubation with 4-methylumbelliferylphosphate (Fisher) supplemented with 2 mM MgCl₂ for 30 minutes. Thereaction was stopped with 0.2M EDTA, and the plate was read at ex=355nm, em=460 nm. Inhibition of MAC deposition was calculated for eachsample relative to baseline (EDTA treated human serum) and positivecontrol (human serum), and used to generate the IC50 curve with PRISM.

Table 5 shows data demonstrating the ability of the Factor P antibodiesto inhibit the deposition of MAC, thus indicating that the antibodiesinhibited the alternative complement pathway. Specifically, theantibodies inhibited MAC deposition with an IC50 of less than or equalto 25 nM.

C3a Deposition Assay

Another method used to assess the ability of Factor P antibodies toinhibit the alternative complement pathway is to measure the ability ofantibodies to inhibit the generation of C3a following cleavage of C3 byC3 convertase. The assay was carried out on zymosan-coated Maxisorpplates coated at 10 mg/ml and 10% and 20% human serum pre-incubated withanti-properdin Fab diluted in a 2^(n) series. The serum was added to theplates for 30 minutes at which time the serum was collected forassessment of C3a generation.

Maxisorp plates were coated with anti-C3a des-arg neo antibody (1 ug/ml)overnight, washed three times, and blocked with diluent for two hours atroom temperature. Following aspiration of the diluent, serum was addedfor one hour. Plates were washed three times and a 100 uL/well detectionantibody Mouse anti-Human C3a-Biotin 1:1000 diluted in diluent wasadded. Following an additional one hour incubation, a streptavidin-HRPsecondary antibody diluted 1:5000 in diluent was added to the wells forone hour at room temperature. Plates were washed four times before theaddition of TMB detection substrate. The reaction was stopped usingstandard stop solution and absorbance was read at 450-570 nm.

In parallel to the addition of the serum, a standard curve was producedusing purified C3a des-arg diluted in serum. Starting at 5 ug/ml, C3ades-arg was serially diluted 1:4 to generate a 7 point curve. Thestandard curve wells were treated, washed, and read as above.

TABLE 5 Functional Analysis of Factor P Antibodies MAC Inhibition Depo-Hemolytic of C3a sition, Zymosan- assay generation, 20% C3b IC50 IC5020% Serum (nM), (nM), human Factor P Factor P EC50 10% 10% serumAntibody Species (nM) serum serum (nM) NVS962 Human 18.79 2.63 13.1878.42 Cyno 12.08 9.91 16.14 ND NVS965 Human 17.32 1.54 7.527 31.33 Cyno22.17 6.36 13.20 ND NVS963 Human ND 2.34 10.11 65.08 Cyno ND 9.75 14.53ND NVS966 Human ND 1.66 7.154 41.11 Cyno ND 6.62 13.00 ND NVS964 HumanND 1.54 9.26 42.18 Cyno ND 6.59 13.41 ND NVS967 Human ND 2.53 9.61 43.53Cyno ND 5.92 14.01 ND NVS962-Q Human 23.12 0.64 15.27 ND Cyno 20.88 1.6214.7 ND NVS962-S Human 6.53 1.53 8.21 ND Cyno 15.57 1.94 12.02 NDNVS962-T Human 6.61 1.75 9.31 ND Cyno 5.42 3.10 12.54 ND NVS962-G Human12.68 1.18 13.39 ND Cyno 9.27 2.94 14.23 ND NVS962-S31A Human 9.96 1.1512.79 ND Cyno 7.86 3.12 11.61 ND NVS965-Q Human 15.40 1.64 9.71 ND Cyno9.39 3.30 14.71 ND NVS965-S Human 7.32 1.39 7.89 ND Cyno 8.12 1.57 12.02ND NVS965-T Human 13.80 0.77 7.15 ND Cyno 10.98 1.91 12.54 ND NVS808Human 6.51 ND 13.28 ND Cyno 8.38 ND 15.53 ND NVS806 Human 5.74 ND 10.14ND Cyno 6.51 ND 13.93 ND NVS807 Human 5.40 ND 12.91 ND Cyno 6.35 ND12.57 ND NVS804 Human 5.85 ND 12.38 ND Cyno 8.51 ND 14.44 ND NVS805Human 5.90 ND 12.82 ND Cyno 5.95 ND 22.11 ND NVS809 Human 6.46 ND 12.1ND Cyno 5.90 ND 12.78 ND ND: Not Determined

Example 5 Species Cross Reactivity

In order to determine whether, in addition to human and cynomolgus, theanti-Factor P antibodies described herein would bind to Factor P fromother species, MAC deposition and hemolytic assays were carried out asdescribed above. BIAcore analysis, or hemolytic assays were carried outas described above. The serum concentrations used for each species wereas follows: 10 and 20% rabbit, 10 and 20% cynomolgus, and 10 and 20%human sera. Rat Factor P binding was assessed by BIAcore. As shown inTable 6 below, the Factor P antibodies were able to cross react withseveral species, including rabbit, rat and cynomolgus.

TABLE 6 Species cross-reactivity Antibody Human Rat Rabbit Cyno NVS962 XX X X NVS962-S X X X X NVS801 X X X X NVS965 X ND ND X NVS965-S X ND NDX NVS808 X ND X X NVS806 X ND X X ND: not determined

Example 6 Epitope Mapping

Factor P is comprised of several Thrombospondin repeat domains (TSR0-6). The TSR0 domain is also referred to as the N terminal domain.Epitope mapping of the Factor P Fabs was performed by creating mouse andhuman chimeras for each TSR. Previous functional assays showed that theFabs do not bind to mouse Factor P (hemolytic assays), although each ofthe chimeras was functional in Factor P-depleted serum. Using thismethod it was determined that all of the Fabs bind to TSR 5 (SEQ ID NO:406). FIG. 1C shows the antibodies bind region B of TSR5. Thecommercially-available antibody, A233, was shown not to bind in thisregion. Binding can be assessed by ELISA or Biacore using standardmethods. For one Ab, NVS487, the data was not conclusive due to crossreactivity to mouse Factor P. Sequence alignment between mouse and humanFactor P TSR5 domain shows the epitope includes the amino acids of SEQID NO: 408.

Example 7 In Vivo Inhibition of the Alternative Complement Pathway

Experiments were performed in cynomolgus money with antibodies of theinvention to determine their ability to inhibit the alternativecomplement pathway.

The test item, NVS962, was administered at the dose levels shown inTable 7. The route of administration was either intravitral (IVT) orintravenous (IV).

TABLE 7 In Vivo Study Design Route Group Group Dose of Dose volumeAnimals/group number description level dosing (μL/injection) Male Female1 Control   0 (vehicle) IVT  50/IVT 1 1 IV injection 100/IV injection 2Low IVT   1 mg/eye IVT  50/IVT 1 1  (2 mg/monkey) injection 3 IV  10mg/monkey IV 100/IV 1 1 injection 4 High IVT   5 mg/eye IVT  50/IVT 1 1(10 mg/monkey) injection

The test item and vehicle solutions (vehicle: 10 mM His/His-HCl; 10%trehalose; 0.02% Tween 20; pH 5.5) were administered intravitreally andintravenously on days 1, 15, and 29 of the study as indicated in Table7.

Assessment of toxicity was based on mortality, clinical observations,body weights, pharmacodynamics (hemolytic analysis), ophthalmicexaminations, intraocular pressure measurements, electroretinography,hematology, clinical chemistry, organ weights, and pathology.

There were no mortalities during the study and no test item relatedfindings were seen after evaluation of clinical signs, body weights,ophthalmic examinations, intraocular pressure measurements,electroretinography, hematology, clinical chemistry, organ weights, andpathology.

Complement mediated hemolytic activity was measured using the hemolyticassay described above (see Example 4). Analysis of the hemolytic assaydata showed that IV administration of NVS962 led to a complete or nearlycomplete but short-lived, inhibition of hemolytic complement activityimmediately after administration. When administered by the IVT route ata dose of 1 mg/eye, the test item had little or no effect on serumhemolytic complement activity. At 5 mg/eye and in 10% cynomolgus serum,a complete or nearly complete inhibition of hemolytic complementactivity was observed.

Example 8 Synergistic Inhibition of the Alternative Complement Pathwayby Antibody Combinations Hemolysis Assay

Hemolytic assays using the Fab versions of the anti-C5 antibody 8109from Table 2 and anti-Factor P antibody NVS962 from Table 1 wereperformed as described in Example 4.

FIG. 2 exemplifies of the ability of the Factor P antibodies and antigenbinding fragments in combinations with anti-C5 antibodies and antigenbinding fragments to inhibit hemolysis in 20% human serum. 500 nManti-factor P and 500 nM anti-C5 Fabs individually demonstrate noinhibition of hemolysis when incubated for 60 mins. In contrast, thecombination of anti-factor P and anti-C5 antibodies at the sameconcentration and at concentrations as low as 167 nM demonstrate nearcomplete inhibition of hemolysis. In addition, the near completeinhibition of hemolysis lasts for up to 250 minutes.

Data from the hemolytic assay was used with Chalice Analyzer software todetermine whether the combination of complement inhibiting antibodiesacted synergistically to block complement activation. Combinationeffects can be characterized by comparing each data point's inhibitionto that of a combination reference model that was derived from thesingle agent curves (Greco, Bravo, Parsons (1995). The search forsynergy: a critical review from a response surface perspective.Pharmacol Rev 47(2): 331-85). In the Loewe additivity model (Loewe(1928). Die quantitativen Probleme der Pharmakologie. Ergebn. Physiol.27: 47-187), I_(Loewe) (C_(X),C_(Y)) is the inhibition that satisfies(C_(X)/C_(X))+(C_(Y)/C_(Y))=1, and IC_(X,Y) are the effectiveconcentrations at I_(Loewe) for the fitted single agent curves. Loeweadditivity is the generally accepted reference for synergy (Greco etal.), as it represents the combination response generated if X and Y arethe same compound.

Potency shifting is usually shown using an isobologram (Greco et al.)which shows how much less drug is required in combination to achieve adesired effect level, when compared to the single agent doses needed toreach that effect. The choice of effect level for the isobologramdisplay and combination index calculations can either be manually orautomatically selected in the Chalice Analyzer. The automatic iso-levelselection algorithm finds the observed I_(data) with the largestI_(data)−I_(Loewe), excluding those points with I_(data) exceeding thelesser single agent's I_(max). This exclusion is applied to ensure thatthe isobologram reflects the best synergy at levels covered by bothsingle agents. Having selected an isobologram level I_(cut), theisobologram is drawn by identifying the locus of concentrations thatcorrespond to crossing the chosen iso-level. The isobologram shows thestandard isobolographic analysis of synergy compared to the Loewedose-additive “drug-with-itself” standard. For a specified isobologramlevel, the observed iso-effect contour (e.g., curved line in FIG. 3) isdisplayed with the theoretical dose-additive contour (e.g., straightline in FIG. 3), on an IC_(effect)-normalized linear concentration scalefor both substances in the combination. The Dose-additive reference isalways a line connecting the two IC_(effect) concentrations. TheIC_(effect) crossing points are found by interpolating the fittedsigmoidal dose response curves.

Potency shifting is scored as the combination index (Chou, Talalay(1984). Quantitative analysis of dose-effect relationships: the combinedeffects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27-55) CI. For a chosen iso-effect level I_(cut),CI_(I)=(C_(X)/EC_(X))_(I)+(C_(Y)/EC_(Y))_(I), where (C_(X)/EC_(X))_(I)for a particular data point is the ratio of the X compound's measuredconcentration to its effective concentration at the chosen inhibitionlevel. The CI can be thought of as a rough estimate of how much drug wasneeded in combination relative to the single agent doses required toachieve the chosen effect level, and a value of 0.1 means that only atenth of equivalent amounts of the single agents were needed for thecombination to reach the same effect level. CI values in the range of0.5-0.7 are typical for in vitro measurements of current clinicalcombinations (Greco et al.). A CI value of 1.0 is indicative of anadditive effect of a combination of antibodies, while a CI value of lessthan 0.5 is indicative of a synergistic effect resulting from theantibody combination. In the Chalice Analyzer, the best CI is reportedfrom the many combination index values calculated for each I_(cut)crossing concentration. Among all the measured CI values, the one withthe largest signal-to-noise level is reported as the best combinationindex.

Data from the hemolytic assay were expressed as % inhibition and loadedinto an 8×8 Excel table, in which the antibodies concentrations wereexpressed as uM values. The Excel template was uploaded to the Chalicesoftware (Lehar et al. 2009) and the combination index was generated bycreating an isobologram curve using IC20 for each antibody(CI=C_(X)/IC_(X)+C_(Y)/IC_(Y), where IC_(X) and IC_(y) are,respectively, the concentrations of anti-factor P antibody and anti-C5antibody alone that result in a 20% inhibition effect and C_(X) andC_(y) are the concentrations of each drug in the mixture that yield 20%inhibition). The combination index at 20% inhibition is 0.36, indicatingsynergy between anti-factor P antibody and anti-C5 antibody (FIG. 3).

Macrophage Infiltration

The effect of anti-fP and anti-C5 Fabs individually or in combinationwere assessed in vivo using the poly-IC murine model of ocularinflammation. Mice were injected i.v. with synthetic dsRNA analog, polyI:C in 0.1 ml PBS systemically into C57BL/6 mice along with anti-fP(antibody NVS962 from Table 1) and anti-C5 antibodies (antibody 8019from Table 2) individually or in combination. Mice were euthanized atindicated time points. Eyes and retinas were collected and proteinextracts were prepared for cytokine and chemokine analysis using amultiplex assay (Pierce). To determine retinal leukocyte infiltration,eyes were fixed in 4% paraformaldehyde and stained with Alexa Fluor-488conjugated F4/80 antibody for macrophages. The retinas were flat mountedwith the retinal vasculature orientated superiorly onto a glass slideand coversliped with a drop of Vectashield mounting medium (VectorLaboratories Inc, Burtingame, Calif.). Fluorescent images of five (500um) regions on each retina were captured using the Axiocam MR3 camera ona Axio.ImageM1 microscope (Zeiss). The number of neutrophils andmacrophages was quantified with Axiovision software (Version 4.5 Zeiss).Using optical coherence tomography (OCT), images of retinas wereobtained and analysed from mice treated with poly I:C. These results(FIG. 4) demonstrate that at the highest concentrations tested (20 ug)no greater than 45% inhibition of macrophage inhibition was observed. Incontrast, combinations of the anti-Factor P and C5 antibodies atconcentrations as low as 2 ug demonstrated 79% inhibition and increasingthe concentration achieved 100% inhibition (compared to only 13% and 32%inhibition respectively for the anti-C5 and anti-Factor P antibodiesindividually).

Data from in vivo poly-IC model (macrophage infiltration) described inthe preceding paragraph were expressed as % inhibition and loaded into a4×4 Excel table, in which the antibody doses were expressed as ugvalues. The Excel template was uploaded to the Chalice analyzer(described above) and the combination index was generated by creating anisobologram curve using IC50 for each antibody(CI=C_(X)/IC_(X)+C_(Y)/IC_(Y), where IC_(X) and IC_(y) are,respectively, the concentrations of anti-factor P antibody and anti-C5antibody alone that result in a 50% inhibition effect and C_(X) andC_(y) are the concentrations of each drug in the mixture that yield 50%inhibition). The combination index at 50% inhibition is 0.42 (See FIG.5), indicating synergy between anti-factor P antibody and anti-C5antibody.

1-47. (canceled)
 48. A composition comprising a first antibody, orantigen binding fragment thereof, that binds Factor P, and a secondantibody, or antigen binding fragment thereof, that binds C5, whereinsaid combination inhibits the alternative complement pathway.
 49. Thecomposition of claim 48, wherein said combination inhibits ocularinflammation.
 50. The composition of claim 48, wherein said ocularinflammation is determined by measuring neutrophil accumulation and/ormacrophage recruitment in the retina.
 51. The combination of claim 48,wherein said combination inhibits neutrophil accumulation in the retina.52. The combination of claim 48, wherein said combination inhibitsmacrophage recruitment in the retina.
 53. The composition of claim 48,wherein said antibody that binds Factor P, binds a region of Factor Pcomprising SEQ ID NO:
 408. 54. The composition of claim 48, wherein saidantibody that binds Factor P, binds a region of Factor P comprising SEQID NO:
 407. 55. The composition of claim 48, wherein said firstantibody, or antigen binding fragment thereof, is an antibody selectedfrom Table 1 and said second antibody or antigen-binding fragmentthereof is an antibody or antigen binding fragment selected from Table2.
 56. The composition of claim 48, wherein the first antibody, orantigen binding fragment thereof binds the same epitope as is anantibody described in Table 1 and the second antibody, or antigenbinding fragment thereof, binds the same epitope as is an antibodydescribed in Table
 2. 57. The composition of claim 48 wherein the firstantibody, or antigen binding fragment thereof comprises a heavy chainvariable region and a light chain variable region, wherein said heavychain variable region CDR1, 2, 3, (HCDR1, HCDR2, and HCDR3) and a lightchain variable region CDR1, 2, 3, (LCDR1, LCDR2, and LCDR3) are selectedfrom the group consisting of: a) HCDR1, HCDR2 and HCDR3 as set forth inSEQ ID NOs: 1, 2, and 3, respectively, and LCDR1, LCDR2, and LCDR3 asset forth in SEQ ID NOs: 4, 5, and 6, respectively; b) HCDR1, HCDR2 andHCDR3 as set forth in SEQ ID NOs: 15, 16, and 17, respectively, andLCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NOs: 18, 19, and 20,respectively; c) HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs: 29,30, and 31, respectively, and LCDR1, LCDR2, and LCDR3 as set forth inSEQ ID NOs: 32, 33, and 34, respectively; d) HCDR1, HCDR2 and HCDR3 asset forth in SEQ ID NOs: 43, 44, and 45, respectively, and LCDR1, LCDR2,and LCDR3 as set forth in SEQ ID NOs: 46, 47, and 48, respectively; e)HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs: 57, 58, and 59,respectively, and LCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NOs:60, 61, and 62, respectively; f) HCDR1, HCDR2 and HCDR3 as set forth inSEQ ID NOs: 71, 72, and 73, respectively, and LCDR1, LCDR2, and LCDR3 asset forth in SEQ ID NOs: 74, 75, and 76, respectively; g) HCDR1, HCDR2and HCDR3 as set forth in SEQ ID NOs: 85, 86, and 87, respectively, andLCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NOs: 88, 89, and 90,respectively; h) HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs: 99,100, and 101, respectively, and LCDR1, LCDR2, and LCDR3 as set forth inSEQ ID NOs: 102, 103, and 104, respectively; i) HCDR1, HCDR2 and HCDR3as set forth in SEQ ID NOs: 113, 114, and 115, respectively, and LCDR1,LCDR2, and LCDR3 as set forth in SEQ ID NOs: 116, 117, and 118,respectively; j) HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs: 127,128, and 129, respectively, and LCDR1, LCDR2, and LCDR3 as set forth inSEQ ID NOs: 130, 131, and 132, respectively; k) HCDR1, HCDR2 and HCDR3as set forth in SEQ ID NOs: 141, 142, and 143, respectively, and LCDR1,LCDR2, and LCDR3 as set forth in SEQ ID NOs: 144, 145, and 146,respectively; l) HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs: 155,156, and 157, respectively, and LCDR1, LCDR2, and LCDR3 as set forth inSEQ ID NOs: 158, 159, and 160, respectively; m) HCDR1, HCDR2 and HCDR3as set forth in SEQ ID NOs: 169, 170, and 171, respectively, and LCDR1,LCDR2, and LCDR3 as set forth in SEQ ID NOs: 172, 173, and 174,respectively; n) HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs: 183,184, and 185, respectively, and LCDR1, LCDR2, and LCDR3 as set forth inSEQ ID NOs: 186, 187, and 188, respectively; o) HCDR1, HCDR2 and HCDR3as set forth in SEQ ID NOs: 197, 198, and 199, respectively, and LCDR1,LCDR2, and LCDR3 as set forth in SEQ ID NOs: 200, 201, and 202,respectively; p) HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs: 211,212, and 213, respectively, and LCDR1, LCDR2, and LCDR3 as set forth inSEQ ID NOs: 214, 215, and 216, respectively; q) HCDR1, HCDR2 and HCDR3as set forth in SEQ ID NOs: 225, 226, and 227, respectively, and LCDR1,LCDR2, and LCDR3 as set forth in SEQ ID NOs: 228, 229, and 230,respectively; r) HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs: 239,240, and 241, respectively, and LCDR1, LCDR2, and LCDR3 as set forth inSEQ ID NOs: 242, 243, and 244, respectively; s) HCDR1, HCDR2 and HCDR3as set forth in SEQ ID NOs: 253, 254, and 255, respectively, and LCDR1,LCDR2, and LCDR3 as set forth in SEQ ID NOs: 256, 257, and 258,respectively; and t) HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs:267, 268, and 269, respectively, and LCDR1, LCDR2, and LCDR3 as setforth in SEQ ID NOs: 270, 271, and 272, respectively.
 58. Thecomposition of claim 48, wherein the first antibody or antigen bindingfragment thereof comprises heavy and light chain variable regions havingamino acid sequences at least 90% identical to SEQ ID NOs: 7 and 8; SEQID NOs: 21 and 22; SEQ ID NOs: 35 and 36; SEQ ID NOs: 49 and 50; SEQ IDNOs: 63 and 64; SEQ ID NOs: 77 and 78; SEQ ID NOs: 91 and 92; SEQ IDNOs: 105 and 106; SEQ ID NOs: 119 and 120; SEQ ID NOs: 133 and 134; SEQID NOs: 147 and 148; SEQ ID NOs: 161 and 162; SEQ ID NOs: 175 and 176;SEQ ID NOs: 189 and 190; SEQ ID NOs: 203 and 204; SEQ ID NOs: 217 and218; SEQ ID NOs: 231 and 232; SEQ ID NOs: 245 and 246; SEQ ID NOs: 259and 260; or SEQ ID NOs: 273 and 274, respectively.
 59. The compositionof claim 48 wherein the first antibody, or antigen binding fragmentthereof comprises a heavy chain variable region comprising SEQ ID NO: 7,21, 35, 49, 63, 77, 91, 105, 119, 133, 147, 161, 175, 189, 203, 217,231, 245, 259, or 273 and a light chain variable region, wherein saidheavy chain variable region and said light chain variable region combineto form an antigen binding site to Factor P.
 60. The composition ofclaim 48, wherein the first antibody, or antigen binding fragmentthereof comprises a light chain variable domain comprising SEQ ID NO: 8,22, 36, 50, 64, 78, 92, 106, 120, 134, 148, 162, 176, 190, 204, 218,232, 246, 260, or 274 and a heavy chain variable domain, wherein thelight chain variable domain and the heavy chain variable domain combineto form an antigen binding site to Factor P.
 61. The composition ofclaim 59, wherein the first antibody or antigen binding fragment thereofcomprises the light chain variable region sequence of SEQ ID NO: 8, 22,36, 50, 64, 78, 92, 106, 120, 134, 148, 162, 176, 190, 204, 218, 232,246, 260, or
 274. 62. The composition of claim 48 wherein the firstantibody, or antigen binding fragment thereof comprises a heavy chain ofSEQ ID NO: 9, 23, 37, 51, 65, 79, 93, 107, 121, 135, 149, 163, 177, 191,205, 219, 233, 247, 261 or 275 and a light chain, wherein the heavychain and the light chain combine to form an antigen binding site toFactor P.
 63. The composition of claim 48, wherein the first antibody,or antigen binding fragment thereof comprises a light chain of SEQ IDNO: 10, 24, 38, 52, 66, 80, 94, 108, 122, 136, 150, 164, 178, 192, 206,220, 234, 248, 262 or 276 and a heavy chain, wherein the light chain andthe heavy chain combine to form an antigen binding site to Factor P. 64.The composition of claim 62, wherein the first antibody or antigenbinding fragment thereof comprises a light chain of SEQ ID NO: 10, 24,38, 52, 66, 80, 94, 108, 122, 136, 150, 164, 178, 192, 206, 220, 234,248, 262 or
 276. 65. The composition of claim 48, wherein the firstantibody, or antigen binding fragment thereof comprises a heavy chainwith an amino acid sequence having at least 90% sequence identity to SEQID NO: 9, 23, 37, 51, 65, 79, 93, 107, 121, 135, 149, 163, 177, 191,205, 219, 233, 247, 261 or 275 and a light chain with an amino acidsequence having at least 90% sequence identity to SEQ ID NO: 10, 24, 38,52, 66, 80, 94, 108, 122, 136, 150, 164, 178, 192, 206, 220, 234, 248,262 or
 276. 66. The composition of claim 48, wherein the first antibody,or antigen binding fragment thereof comprises a heavy chain and a lightchain with an amino acid sequence having at least 90% sequence identity,respectively, to SEQ ID NO: 9 and 10, 23 and 24, 37 and 38, 51 and 52,65 and 66, 79 and 80, 93 and 94, 107 and 108, 121 and 122, 135 and 136,149 and 150, 163 and 164, 177 and 178, 191 and 192, 205 and 206, 219 and220, 233 and 234, 247 and 248, 261 and 262, or 275 and
 276. 67. Anisolated nucleic acid molecule comprising a nucleotide sequence encodingthe first antibody or fragment of claim
 48. 68. An isolated nucleic acidmolecule comprising nucleotide sequence encoding the second antibody orantigen binding fragment thereof of claim
 48. 69. A vector comprisingthe nucleic acid molecule of claim 67
 70. An isolated host cellcomprising the vector of claim
 69. 71. A method of treating age relatedmacular degeneration in a subject comprising administering to saidsubject, an effective amount of the composition of claim
 48. 72. Themethod of claim 71 wherein the subject is human.
 73. A method ofinhibiting the alternative complement pathway in a subject comprisingadministering to said subject an effective amount of the composition ofclaim
 48. 74. The method of claim 73, wherein said subject is human. 75.The composition of claim 48, wherein the second antibody or antigenbinding fragment thereof comprises a heavy chain variable region and alight chain variable region, wherein said heavy chain variable regionCDR1, 2, 3, (HCDR1, HCDR2, and HCDR3) and a light chain variable regionCDR1, 2, 3, (LCDR1, LCDR2, and LCDR3) are selected from the groupconsisting of: a) HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs:410, 411, and 412, respectively, and LCDR1, LCDR2, and LCDR3 as setforth in SEQ ID NOs: 413, 414, and 415, respectively; b) HCDR1, HCDR2and HCDR3 as set forth in SEQ ID NOs: 426, 427, and 428, respectively,and LCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NOs: 429, 430, and431, respectively; c) HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs:442, 443, and 444, respectively, and LCDR1, LCDR2, and LCDR3 as setforth in SEQ ID NOs: 445, 446, and 447, respectively; d) HCDR1, HCDR2and HCDR3 as set forth in SEQ ID NOs: 426, 458, and 428, respectively,and LCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NOs: 429, 430, and459, respectively; and e) HCDR1, HCDR2 and HCDR3 as set forth in SEQ IDNOs: 470, 471, and 472, respectively, and LCDR1, LCDR2, and LCDR3 as setforth in SEQ ID NOs: 473, 474 and 475, respectively.
 76. The compositionof claim 57, wherein the second antibody or antigen binding fragmentthereof comprises a heavy chain variable region and a light chainvariable region, wherein said heavy chain variable region CDR1, 2, 3,(HCDR1, HCDR2, and HCDR3) and a light chain variable region CDR1, 2, 3,(LCDR1, LCDR2, and LCDR3) are selected from the group consisting of: a)HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs: 410, 411, and 412,respectively, and LCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NOs:413, 414, and 415, respectively; b) HCDR1, HCDR2 and HCDR3 as set forthin SEQ ID NOs: 426, 427, and 428, respectively, and LCDR1, LCDR2, andLCDR3 as set forth in SEQ ID NOs: 429, 430, and 431, respectively; c)HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs: 442, 443, and 444,respectively, and LCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NOs:445, 446, and 447, respectively; d) HCDR1, HCDR2 and HCDR3 as set forthin SEQ ID NOs: 426, 458, and 428, respectively, and LCDR1, LCDR2, andLCDR3 as set forth in SEQ ID NOs: 429, 430, and 459, respectively; ande) HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NOs: 470, 471, and 472,respectively, and LCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NOs:473, 474 and 475, respectively.
 77. The composition of claim 48, whereinthe second antibody or antigen binding fragment thereof comprises heavyand light chain variable regions having amino acid sequences at least90% identical to SEQ ID NOs: 416 and 417; SEQ ID NOs: 432 and 433; SEQID NOs: 448 and 449; SEQ ID NOs: 460 and 461; or SEQ ID NOs: 476 and477, respectively.
 78. The composition of claim 58, wherein the secondantibody or antigen binding fragment thereof comprises heavy and lightchain variable regions having amino acid sequences at least 90%identical to SEQ ID NOs: 416 and 417; SEQ ID NOs: 432 and 433; SEQ IDNOs: 448 and 449; SEQ ID NOs: 460 and 461; or SEQ ID NOs: 476 and 477,respectively.
 79. The composition of claim 48, wherein the secondantibody or antigen binding fragment thereof comprises a heavy chainvariable region comprising SEQ ID NO: 416, 432, 448, 460 or 476 and alight chain variable region, wherein said heavy chain variable regionand said light chain variable region combine to form an antigen bindingsite to C5.
 80. The composition of claim 59, wherein the second antibodyor antigen binding fragment thereof comprises a heavy chain variableregion comprising SEQ ID NO: 416, 432, 448, 460 or 476 and a light chainvariable region, wherein said heavy chain variable region and said lightchain variable region combine to form an antigen binding site to C5. 81.The composition of claim 48, wherein the second antibody or antigenbinding fragment thereof comprises a light chain variable regioncomprises a light chain variable domain comprising SEQ ID NO: 417, 433,449, 461 or 477 and a heavy chain variable domain, wherein the lightchain variable domain and the heavy chain variable domain combine toform an antigen binding site to C5.
 82. The composition of claim 60,wherein the second antibody or antigen binding fragment thereofcomprises a light chain variable region comprises a light chain variabledomain comprising SEQ ID NO: 417, 433, 449, 461 or 477 and a heavy chainvariable domain, wherein the light chain variable domain and the heavychain variable domain combine to form an antigen binding site to C5. 83.The composition of claim 59, wherein the second antibody or antigenbinding fragment thereof comprises the light chain variable regionsequence of SEQ ID NO: 417, 433, 449, 461 or
 477. 84. The composition ofclaim 61, wherein the second antibody or antigen binding fragmentthereof comprises the light chain variable region sequence of SEQ ID NO:417, 433, 449, 461 or
 477. 85. The composition of claim 48, wherein thesecond antibody or antigen binding fragment thereof comprises a heavychain of SEQ ID NO: 418, 434, 450, 462, or 478 and further comprises alight chain, wherein the heavy chain and the light chain combine to forman antigen binding site to C5.
 86. The composition of claim 62, whereinthe second antibody or antigen binding fragment thereof comprises aheavy chain of SEQ ID NO: 418, 434, 450, 462, or 478 and a light chain,wherein the heavy chain and the light chain combine to form an antigenbinding site to C5.
 87. The composition of claim 48, wherein the secondantibody or antigen binding fragment thereof comprises a light chain ofSEQ ID NO: 419, 435, 451, 463, or 479 and a heavy chain, wherein thelight chain and the heavy chain combine to form an antigen binding siteto C5.
 88. The composition of claim 63, wherein the second antibody orantigen binding fragment thereof comprises a light chain of SEQ ID NO:419, 435, 451, 463, or 479 and a heavy chain, wherein the light chainand the heavy chain combine to form an antigen binding site to C5. 89.The composition of claim 62, wherein the second antibody or antigenbinding fragment thereof comprises a light chain of SEQ ID NO: 419, 435,451, 463, or
 479. 90. The composition of claim 64, wherein the secondantibody or antigen binding fragment thereof comprises a light chain ofSEQ ID NO: 419, 435, 451, 463, or
 479. 91. The composition of claim 48,wherein the second antibody or antigen binding fragment thereofcomprises a heavy chain with an amino acid sequence having at least 90%sequence identity to SEQ ID NO: 418, 434, 450, 462, or 478 and a lightchain with an amino acid sequence having at least 90% sequence identityto SEQ ID NO: 419, 435, 451, 463, or
 479. 92. The composition of claim65, wherein the second antibody or antigen binding fragment thereofcomprises a heavy chain with an amino acid sequence having at least 90%sequence identity to SEQ ID NO: 418, 434, 450, 462, or 478 and a lightchain with an amino acid sequence having at least 90% sequence identityto SEQ ID NO: 419, 435, 451, 463, or
 479. 93. The composition of claim48, wherein the second antibody or antigen binding fragment thereofcomprises a heavy chain and a light chain with an amino acid sequencehaving at least 90% sequence identity, respectively, to SEQ ID NOs: 418and 419, 434 and 435; 450 and 451; 462 and 463; or 478 and
 479. 94. Thecomposition of claim 66, wherein the second antibody or antigen bindingfragment thereof comprises a heavy chain and a light chain with an aminoacid sequence having at least 90% sequence identity, respectively, toSEQ ID NOs: 418 and 419, 434 and 435; 450 and 451; 462 and 463; or 478and 479.